Welcome to the Open Learning Initiative Introduction to Anatomy and Physiology course!

We are happy that you have decided to introduce yourself to this important field, and we hope that your learning experience will be an enriching and enjoyable one.

The purpose of this introductory section is to prepare you conceptually and technically for this course. We will start with a short orientation to the course, including some learning strategies that will explain a little about how the course works and give you some pointers on how to use the material most efficiently.

We will then discuss what Anatomy and Physiology is all about—the "Big Picture" of Anatomy and Physiology—and look at how the major themes discussed in the Big Picture tie in to the material presented in the course.

Our intention is for you to begin to think and speak in the language of the domain while integrating the knowledge you gain about anatomy to support explanations of physiological phenomenon. The course focuses on a few themes derived from the Big Ideas, that when taken together, provide a full view of what the human body is capable of and the exciting processes going on inside of it. The themes are:

• Structure and function of the body, and the connection between the two.
• Homeostasis, the body’s natural tendency to maintain a stable internal environment.
• Levels of Organization, the major levels of organization in the human organism from the chemical and cellular levels to the tissues, organs and organ systems.
• Integration of Systems, concerning which systems are subsets of larger systems, and how they function together in harmony and conflict.

You can see how these themes directly relate to the Big Ideas. As these themes are used to describe the inner workings of each of the body’s organ systems, those can be categorized into the specific vital functions for human life. The vital functions provide the context for the whole body, and how each organ system plays a role in keeping us alive. So, the information provided for each of the organ systems is organized according to those functions that are essential to the survival of the human body. The vital functions for human life are:

• Exchange of substances and information with the environment
• Transport within the body
• Structure, support, and movement
• Control and regulation
• Growth and reproduction

All multicellular organisms need these vital functions to operate properly in order to survive. In addition to understanding the Themes and Vital Functions, knowing body planes and directional terms will also help you in your quest for Anatomy and Physiology mastery.

Everyone has a body and, by adulthood, a general understanding of how it works. But to truly understand the intricate functions of the human body—and the problems that occur when something goes wrong—you must approach the study of the body in an organized way. This course will help you understand the functions of the human body. The course will discuss the details of many complex functional systems, but will also look at how all of these systems work in harmony to keep you healthy. As you move through this course, you should keep four main themes in mind: structure and function, homeostasis, levels of organization, and integration of systems.

In this section, you will be introduced to the major organ systems of the body. To put these systems in context, we will first discuss vital functions of life.

Within any organism, there are a multitude of functions taking place at any given time. Humans, for example, can breathe, talk, digest food, process visual images, and move their bodies all at the same time. While all of these activities are important, some are essential to the survival of the human body itself. They are vital functionsOur body's anatomy and physiology works together to perform the vital functions that keep us alive - processes or actions of the body on which life is directly dependent. You will examine four main vital functions in this course: exchange with the environment; transport within the body; structure, support, and movement; and control and regulation.

For human life, there are several vital functions.

So you now know that all multicellular organisms need to do the following in order to survive:

• Exchange with the environment
• Transport fluids and material throughout the body
• Provide structure, support, protection and movement
• Regulate and control processes

So what does this mean? What does this involve? How does the human body do these things? Try answering the questions below to begin broadly thinking about bodily function within these categories and how they are linked to one of the primary organ systems.

Several organ systems control these various vital functions throughout the body. Since the organ systems control large regions of the human body, it is necessary to define orientation within the body and communicate the proper terminology as you study these integrated structures and functions.

You can use other terms to further pinpoint an anatomical location. These terms are used to describe a location in relation to other structures. Some of them may be terms you have heard in everyday conversation; a lateral pass in football, for example, is a pass toward the sideline.

The following table lists all of the human anatomical directions that we discussed. You will practice using these planes and directional terms when describing the locations of organs and organ systems in the following sections.

Now that you have reviewed ways to describe location and orientation, you will learn about the organ systems that are necessary for the vital functions of life. You will also get a chance to practice using body planes and directional orientations to explain the anatomical integration and relative location of structures within organ systems. The next section will systematically describe the organ systems of the body, as well as the major anatomical structures and functions.

The major organ systems of the body are shown in the table below.

The sections that follow will describe the details of the organ systems that perform the vital functions of life. You will learn how they contribute to homeostasis and how imbalances in homeostasis lead to various disease states.

Life is a complex continuum of flows of energy and matter. Discrete structures such as organs and cells allow us to divide life into levels of organization. This organization is to some extent artificial, and to some extent practical.

The human body is a complex, hierarchical system—that is, a system made up of smaller subsystems, which are themselves made up of even smaller systems. We commonly study these different hierarchical levels—levels of organization—separately. By breaking down the complex system into simpler parts, we can make the whole system easier to understand. This “reductionist” approach, reducing a complex system to simpler components, is central to how we practice modern science.

Regarding the body, therefore, we consider the body as a whole, then its subsystems, and then the components of these subsystems. We can model the hierarchy of organization within the body as comprised of organs, tissues, cells, cell organelles, macromolecules, molecules and finally atoms.

The levels of organization that we will consider in this course are, from smallest to largest:

• The chemical level, which consists of atoms, ions, and small molecules
• The macromolecule level, which consists of large molecules
• The cell level, which consists of individual cells; this is the smallest level that contains living entities
• The tissue level, which consists of groups of related cells working together to perform a specific function
• The organ level, which consists of groups of tissues working together to perform a higher-level function
• The organ system level, which consists of all of the organs involved in performing a vital function
• The organism or whole body level, which consists of a whole person
• The population or environment level, which involves the interactions of the person with his or her environment

Although we will consider each level individually, it is important for you to keep in mind the connections between the levels. Processes and events at one level can affect other levels. An alteration in the structure of a protein (macromolecule level) can prevent a cell from functioning properly; this improper function can affect the tissues, organs, organ systems, and the whole body. And the reverse is true: changes to the body (organism level) can affect organs, tissues, cells and molecules.

For example, suppose a single nitrogenous base in DNA (chemical level) is incorrect. This mutation causes an alteration in the structure of the beta globin (β-globin) protein (macromolecule level), which is part of hemoglobin. The altered structure of β-globin causes the proteins to stick together and form fiber-like structures. Under certain physiological conditions, the fibers in turn distort the shape of red blood cells (cell level), so that the cells become curved and twisted. The abnormal cells get stuck in capillaries, reducing blood flow to tissues and organs (tissue and organ levels). Organ damage may result, permanently affecting body function (whole body level).

This example describes sickle cell anemia, a genetic blood disorder. We can clearly see the connections between levels of organization. A seemingly tiny error at the genetic (chemical) level causes significant changes in the body’s systems at higher levels. Many genetic diseases arise in this way—through small alterations in the genetic code.

But scientists are homing in on the genetic basis for some diseases, such as cancer. In some instances, our understanding may hint at genetic therapies for a disease. Such technology is still largely experimental, but it shows the practical value of looking at the levels of organization of complex systems.

At every level of organization, structure is related to function. For example water is able to peform many of its unique and life-sustaining properties because of its structure. It is a bent polar molecule that can form attractions with neighboring water molecules through hydrogen bonds. At the macromolecular level, the unique structures of enzymes allow these proteins to help speed up reactions. On the cell and tissue level, the rigid matrix structure of your bones allows them to be able to support the weight of your body. At the organ level, the "J" shape of the stomach allows for partial segregation of its contents at the early stages of digestion.

Look around you. Everything is made of chemicals of one sort or another. Life is chemistry organized into astonishing complexity and intricacy. To make sense of this organization we can look at life’s chemistry as a hierarchy—levels of organization. From simple elemental ions, to simple organic molecules, complexity rises with increasingly larger macromolecules.

A person is between 1-2 meters (m) tall, but there are many length scales and biological levels of detail which are important for understanding anatomy and physiology. For perspective on size difference, considered an atomAtoms are basic units of matter. Atoms contain a positive center (nucleus) surrounded by a cloud of electrons that allow interatomic interactions. at 10^-10 m. We can’t really grasp how small that is, but think big instead of small. A length of 10¹⁰ m is more than the distance from the Earth to the moon.

The smallest length scale that we will cover is the size of individual atoms, but the movement of subatomic particles called electrons, can change atomic charge. Ions are atoms that carry either a positive or negative charge from altered numbers of electrons, and many atoms and molecules exist in the body as ions.

Ionic chemistry is important in human medicine and health. Ions play an essential role in physiological processes, particularly in cell membranes. Sodium, potassium and calcium ions are required for nerve impulses and heart beats, enable cell-to-cell communication and initiate cellular processes. For example, release of insulin by beta cells of the pancreas is mediated by ions. Transport of ions across membranes may occur by passive diffusion, through ion channels, or through pumps. Pumps often move ions against a concentration gradient. Ionic chemistry is important in human medicine. Anesthetic drugs such as Novocain block sodium channels. Neurotoxins from some snakes and puffer fish work by blocking ion movements in nerve transmission. Malfunctions in ionic channel or pump molecules can result in serious physiological ailments, including cystic fibrosis (mutation in a gene that codes for cell membrane chloride channel) and epilepsy.

Even subatomic particles, which are too small to see with the best microscopes in the world, play an extremely important role in maintaining proper physiology.

The key biologically relevant elements are hydrogen (H), carbon (C), nitrogen (N), oxygen (O), phosphorous (P) and sulfur (S). These elements represent more than 95 percent of the mass of a cell. Carbon is a major component of nearly all biological molecules.

Elements are characterized by their atomic structure. While the subatomic structure of the atom is a major topic of interest in chemistry, physics and biophysics, we will only discuss the basic structure that will provide sufficient information for the construction of molecules in the context of this course. Atoms have a central nucleus with positively charged protons and neutral neutrons; negatively charged electrons circle the nucleus. The electrons that are involved in chemical bonding are those electrons in the outermost orbit, referred to as valence electrons. On the periodic table below, you can view each of the atoms while hiding all but the outermost electrons.

Atomic mass, the sum of the number of protons and neutrons in the atomic structure, is a particularly useful measure of each element. By summing the atomic mass of all the atoms in a molecule, one can estimate the molecular mass of the molecule, which is then expressed in atomic mass units, or Daltons. This table shows the masses of the six atoms of the elements listed above, which can also be found in the upper right-hand corner of the box for each element in the periodic table.

To calculate the mass of a molecule, we find the mass of each individual atom in the molecule and add them together. For example, a water molecule (H₂O) contains one oxygen atom that has a mass of 16 amu (atomic mass units) and two hydrogen atoms that each have a mass of one amu. Therefore, the mass of a water molecule is 16 amu + 2 X 1 amu = 18 amu.

The electronegativity of an element is the degree to which an atom will attract electrons in a chemical bond. Elements with higher electronegativities, such as N, O and F (fluorine), have a strong attraction for electrons in a chemical bond and will therefore “pull” electrons away from less electronegative atoms. Elements with low electronegativity, such as metals, tend to “give away” electrons easily.

Water is the basis of life. Without it, life is not possible. Water accounts for up to 75 percent of the weight of the human body. Water provides a relatively stable medium in which chemical reactions can take place. Water’s unique chemical properties (as a solvent with a high boiling point and high heat capacity) make it essential for homeostasis. The body’s thermoregulation relies on water’s high heat capacity to buffer it against swings in external temperature. Cooling of the body is carried out by evaporative water loss—perspiration. Water is also vital as a transport medium. Oxygen is carried by red blood cells suspended in serum, which is mostly water. Nutritional substances are dissolved in water and transported to cells. Water is used to dissolve and dilute waste molecules. If the body is deprived of water for very long, death will result.

Water has several properties that contribute to its suitability to support life as we know it. One of these properties is that water is a polar molecule. Oxygen is more electronegative than hydrogen and draws the electrons that it shares in the covalent bond towards itself. Because water is polar, the partial positive end of one water molecule will be attracted to the partial negative end of a neighboring water molecule. This attraction is called a hydrogen bond. Hydrogen bondingThe attraction of an atom with high electronegativity for a hydrogen atom that is covalently bonded to another highly electronegative atom. This involves the attraction of a hydrogen atom with a partial positive charge to an atom with a partial negative charge. Only hydrogen atoms covalently bonded to a highly electronegative atom can participate in hydrogen bonding. occurs between partially negatively charged atoms with high electronegativity—oxygen, nitrogen or fluorine—and partially positively charged hydrogen atoms that are bonded to oxygen, nitrogen or fluorine atoms.

Hydrogen bonding, which is referred to as an intermolecular attraction, is a critical interaction within the cell. It is the principal force that holds the tertiary structure of proteins, carbohydrates and nucleic acids together and the overall stability of these molecules is due in part to the cumulative effect of the large number of hydrogen bonds found in the functional structures. Hydrogen bonds are found in and between a variety of molecules. For example, the enormous number of hydrogen bonds between strands of plant cellulose provide the strength and structure of the plant cell wall. As another example, wool (sheep hair) has lots of proteins with an enormous number of hydrogen bonds that provide the curly structure of individual wool fibers. These curly fibers trap air spaces which makes wool such a good insulator. When washed at high temperatures, these hydrogen bonds are broken and the wool fibers will lose their shape, probably damaging any wool clothing.

A water molecule attracts four other water molecules towards itself. One molecule to each of the two free pairs of electrons in the oxygen atom valence shell, and one to each of the hydrogen atoms covalently bonded to the oxygen. As the water molecules associate with each other they have a defined structure dictated by the tetrahedral geometry of the electrons around the oxygen atom as seen in the figure below. The partially positive hydrogen atoms are attracted to the free electron pairs from other water molecules while the partially negative charge on the oxygen's free electron pairs are attracted to the partially positive hydrogen atoms from another water molecule.

After nucleic acids, proteins are the most important macromolecules. Structurally, proteins are the most complex macromolecules. A protein is a linear molecule comprised of amino acids. Twenty different amino acids are found in proteins. The sequence of a protein's amino acids is determined by the sequence of bases in the DNA coding for the synthesis of this protein. A single protein molecule may be comprised of hundreds of amino acids. This sequence of amino acids is a protein's primary structure. The protein's size, shape and reactive properties depend on the number, type and sequence of amino acids. The amino acid chain can remain in its primary linear structure, but often it folds up and in on itself to form a shape. This Secondary structure forms from localized interactions (hydrogen bonding) of amino acid side chains. These include alpha helix and beta sheet structures. The alpha helix is dominant in hemoglobin, which facilitates transport of oxygen in blood. Secondary structures are integrated along with twists and kinks into a three-dimensional protein. This functional form is called the tertiary structure of the protein. An additional level of organization results when several separate proteins combine to form a protein complex—called quaternary structure.

Proteins perform numerous essential functions within the cell. Many proteins serve as enzymes, which control the rate of chemical reactions, and hence the responsiveness of cells to external stimuli. An enzyme can fast-forward a reaction that would take millions of years under normal conditions and make it happen in just a few milliseconds. Enzymes are important in DNA replication, transcription and repair. Digestive processes are also largely facilitated by enzymes, which break down molecules that would otherwise be too large to be absorbed by the intestines. Enzymatic proteins also play a role in generation and transmission of nerve impulses, for example helping to generate muscle contractions.

Other proteins are important in cell signaling and cell recognition. Receptor proteins recognize substances as foreign and initiate an immune response. Through cell signaling, proteins mediate cell growth and differentiation during development. Several important proteins provide mechanical support for the cell, scaffolding that helps the cell maintain its shape. Other proteins comprise much of the body’s connective tissue and structures such as hair and nails.

For protein production in cells the body needs amino acids, which we ingest. It seems a bit inefficient, but we eat proteins, break them down into amino acids, distribute the amino acids inside the body and then build up new proteins. Our cells can synthesize some amino acids from similar ones, but essential amino acids must be obtained from the diet, since they cannot be synthesized. Deficiencies of protein in the diet result in malnutrition diseases such as kwashiorkor, which is common in developing countries. In cases of kwashiorkor, protein deficiency causes edema (swelling) which leads to a distended abdomen. Excess protein is metabolized into ammonia and urea, which are typically excreted—up to a point. When too much urea accumulates it cannot be filtered by the kidneys. Urea accumulation can cause yellowing of the skin.

Unlike nucleic acids, which must remain unchanged in the body for the life of the organism, proteins are meant to be transient—they are produced, do their functions and then are recycled. Proteins are also readily broken down by extremes of heat or pH. When you boil an egg, the yolk and white stiffen and change color. When you cook meat, the flesh changes color and becomes firm. These changes arise because the constituent proteins are “denatured” and have lost their secondary and tertiary structures.

Primarily located in the cell nucleus (hence the name) nucleic acidsOrganic, replicating macromolecules that include RNA and DNA. are replicating macromolecules. The most important are DNA and RNA. Without them, cells could not replicate; life would not be possible. These molecules store the cell’s “software”—the instructions that govern its function, processes and structure. The code is comprised of sequences of four bases—adenine, cytosine, guanine and thymine (uracil in RNA). These are arranged in sets of three called triplets. Each triplet specifies an amino acid, which in turn is a component of a protein macromolecule. All the intricate complexity of the human body arises from the information encoded by just four chemicals in a single long DNA macromolecule.

In humans, mistakes in the structures of DNA and RNA cause diseases, including sickle cell anemia, hemophilia, Huntingdon's chorea and some types of cancer. Even a small error can result in a dramatic effect. Sickle cell disease is caused when just one amino acid in the DNA base sequence is changed. Through directing chemical processes, nucleic acids instruct cells how to differentiate into various organs. During development, whole sets of DNA sequences are shut down or activated to drive specific processes. These processes lead to different kinds of cells that form organs such as the heart, liver, skin and brain.

Within the cell, nucleic acids are in turn organized into higher-level structures called chromosomes. You can see chromosomes with a light microscope, using an appropriate stain. Early study of chromosomes helped scientists discover and understand the role of nucleic acids in cellular reproduction. Errors in chromosomal structure lead to malfunctions of life processes. For example, in humans, an extra chromosome 21 results in Down Syndrome.

The Backbone

Structure of RNA and DNA

Our genetic code is determined by only four bases in DNA (G, C, A, T), which are repeated and arranged in a special order. For example,

1 agccctccag gacaggctgc atcagaagag gccatcaagc agatcactgt ccttctgcca

61 tggccctgtg gatgcgcctc ctgcccctgc tggcgctgct ggccctctgg ggacctgacc

121 cagccgcagc ctttgtgaac caacacctgt gcggctcaca cctggtggaa gctctctacc

181 tagtgtgcgg ggaacgaggc ttcttctaca cacccaagac ccgccgggag gcagaggacc

241 tgcaggtggg gcaggtggag ctgggcgggg gccctggtgc aggcagcctg cagcccttgg

301 ccctggaggg gtccctgcag aagcgtggca ttgtggaaca atgctgtacc agcatctgct

361 ccctctacca gctggagaac tactgcaact agacgcagcc cgcaggcagc cccacacccg

421 ccgcctcctg caccgagaga gatggaataa agcccttgaa ccagcaaaa

This may seem like a random string of G, C, A, T, but this DNA codes for human insulin. DNA is organized into a linear polymer in a double helix and maintains the inherited order of bases or genetic code. The "steps" of the DNA ladder have the code that ultimately directs the synthesis of our proteins. This linear polymer of genetic code is maintained when double strand DNA is transcribed to single strand RNA.

Structure of a nucleotide

The fundamental unit of DNA is the nucleotide. The nucleotide contains a phosphate group (shown in orange), which will eventually give the DNA polymer its charge and interconnect nucleotides on the backbone. The furanose sugar group is a five-sided sugar (shown in purple). The nitrogenous base (shown in yellow) gives the DNA its specificity.

The numbering of the positions on the sugar furanose rings of DNA and RNA follow a convention that uses ' (the prime symbol) to denote the sugar positions. Thus, the ribose has a nitrogenous base connected to the 1' position and hydroxyl groups (OH) on the 2', 3' and 5' positions. Using this nomenclature, deoxyribose is formally called 2'-deoxyribose (2 prime deoxyribose) to denote the loss of the hydroxyl at the 2' position of ribose.

The major difference in the polymer backbones between DNA and RNA is the sugar used in the formation of the polymer. In DNA (DeoxyriboNucleic Acid) the 2' position of the furanose has a hydrogen. In RNA (RiboNucleic Acid), the 2' position of the furanose has an OH (hydroxyl) and the sugar is the monosaccharide ribose in the furanose conformation.

Furanose sugars

The linkage of individual nucleotides is made by a bridging phosphate molecule between two hydroxyl groups, one on each furanose ring. The resulting polymer is a string of furanose molecules linked by phosphodiester bonds in one very long macromolecule.

Backbone of DNA

The following is a list of structural characteristics of the DNA/RNA polymer backbone.

• Phosphate-ribose(deoxyribose)-phosphate-ribose(deoxyribose) sequence
• Linked by Phosphodiester covalent bonds
• 3' position on one ribose(deoxyribose) linked to 5' position of adjacent ribose(deoxyribose) through phosphodiester bridge
• Chain has 3' end and 5' end

DNA Transcription

DNA replication: Every time a cell divides, all of the DNA of the genome is duplicated (called replication) so that each cell after the division (called a daughter cell) has the same DNA as the original cell (called the mother cell).

DNA transcription: For the genetic code to become a protein, it goes through a transcription step. DNA is transcribed into RNA (a single-strand nucleic acid). The RNA is then shuttled away from the DNA to the region of protein synthesis.

RNA translation: RNA is translated from a nucleic acid code into the amino acid sequence of a protein.

Thus, the DNA gene code is able to duplicate to maintain consistency throughout the person's body and throughout the person's life. DNA is also used to make proteins through the use of an RNA intermediate.

Lipids include fats and waxes. Several vitamins, such as A, D, E and K, are lipid soluble. Perhaps the most important role of lipids is in forming the membranes of cells and organelles. In this way, lipids enable isolation and control of chemical processes. They also play a role in energy storage and cell signaling.

Lipid molecules forming cell membranes are comprised of a hydrophilic “head” and hydrophobic “tail” (remember, "hydro" means water and "philos" means love; "hydro" means water, "phobic" means fear). A phospholipid bilayer is formed when the two layers of phospholipid molecules organize with the hydrophobic tails meeting in the middle. Scientists believe that the formation of cell-like globules of lipids was a vital precursor to the origin of cellular life, since membranes physically separate intracellular components from the extracellular environment. Thus, lipid membranes enclose other macromolecules, confine volumes to increase the possibility of reaction, and protect chemical processes. Proteins with hydrophobic regions float within the lipid bilayer. These molecules govern transport of charged or lipophobic molecules in and out of the cell, such as energy molecules and waste products. Carbohydrate molecules jutting out of the membrane are important for cell recognition as mentioned previously.

Lipids are also vital energy storage molecules. Carbohydrates can be used right away, and lipids provide long-term energy storage. Lipids accumulate in adipose cells (fat cells) in the body. As part of the catabolic process, from the days when humans had to forage for food, excess carbohydrates can be converted into lipids, which are then stored in fatty tissue. Ultimately, too many ingested carbohydrates and lipids lead to obesity.

Cells are the basis of life—the basic structural unit of living things. Molecules such as water and amino acids are not alive but cells are! All life is comprised of cells of one type or another.

One of the hallmarks of living systems is the ability to maintain homeostasis, or a relatively constant internal state. The cell is the first level of complexity able to maintain homeostasis, and it is the unique structure of the cell that enables this critical function.

In this section of the course, you will learn about the cell and all the parts that make it functional. You will also focus on the cell membrane, which is the structure that surrounds the cell and separates its internal environment from the external environment. It is a critical component because it controls what can enter and exit the cell. This section will also describe how cells reproduce to maintain homeostasis.

The current cell theory states that:

1. All known living things are composed of one or more cells.
2. All new cells are created by pre-existing cells dividing in two.
3. The cell is the most basic unit of structure and function in all living organisms.

Modern cell theorists assert that all functions essential to life occur within the cell; and that, during cell division, the cell contains and transmits to the next generation the information necessary to conduct and regulate cell functioning.

Let’s begin our study of the cell by investigating the basic anatomy of an animal cell. Each cell consists of three components shown in the image above.

1. A cell membrane which surrounds and protects the cell
2. The cytoplasm which is the watery interior of the cell which contains ions, proteins, and organelles
3. Organelles which carry out all activities necessary for the cell to live, grow, and reproduce

Within the body, cells represent a level of organization between organelles and tissues. Organelles in turn are comprised of specialized macromolecules and tissues are collections of specialized cells. Brain, kidney, liver, muscle and lung tissues differ from each other because of the structure and function of their constituent cells. Thus, the cells comprising each tissue type vary in shape, size and interior structure to permit their specific physiological function within the tissue.One important concept to keep in mind as you study anatomy and physiology is that structure determines function. When you look at the shape of a cell, it gives you a clue as to it’s function.

Each cell process is carried out in a specific location in the cell, often located in or around an organelle. Think of an organelle as a level of organization between macromolecules and the cell. Organelles carry out specialized tasks within the cell, localizing functions such as replication, energy production, protein synthesis, and processing of food and waste. The various cells differ in the arrangement and number of organelles, as well as structurally, giving rise to the hundreds of cell types found in the body.

The focus of this section is to understand the organelles of the cell, how they interact with each other, and how they function during transport, growth and division in the cell. You will learn about the controlled chemical environment a cell maintains and what restrictions this places on the types of chemical reactions it can perform. This background is vital to understanding key processes such as how a cell releases energy from glucose, makes and folds proteins, and goes through growth and cell division.

Think of a city and the various jobs within a city. A cell is similar with each organelle serving a specific purpose. There are organelles whose job is to provide shape and structure to the cell, much like the city streets and bridges. These protein rich organelles include intermediate filaments, microtubules, and microfilaments. Some of these actually move other organelles around the cell or change the shape of the cell. When a muscle cell contracts or shortens it does so by the microfilaments made up of the proteins actin and myosin. One special organelle composed of microtubules is located in an area near the nucleus, the centrosome. The centrosome contains a pair called of microtubule bundles known as the centrioles. Centrioles are important because they move chromosomes to opposite ends of the cell during cell replication termed mitosis. Neurons do not have centrioles and cannot replicate.

Other organelles help synthesize the proteins needed by the cell. These protein factories are called ribosomes. They can be scattered within the cell or attached to a membrane channel system called the endoplasmic reticulum or ER. When the ER has ribosomes attached to it, it is termed the rough ER (the ribosomes give it a rough or grainy appearance). When the ER lacks ribosomes it is termed the smooth ER and functions for lipid synthesis and storage of toxins. When a protein is manufactured it must be folded into a specific shape to work. Often additional side chains of carbohydrates must be attached. The protein is processed in the rough ER. Once it is formed it enters the golgi apparatus which is the distributing plant for the cell. It completes any protein processing and then packages it into a vesicle for transport to its destination. Some proteins are needed in the cell membrane and the vesicles make sure they reach the membrane. The golgi apparatus also makes a special type of vesicle termed a lysosome. The lysosome is the garbage man of the cell. It takes in cell debris and waste and destroys it. The lysosome contains very powerful hydrolytic enzymes to accomplish this. It is very important that the enzymes remain in the lysosome or they would destroy the cell.

The power plant of the cell is the mitochondria. This organelle generates the ATP or energy for the cell. Mitochondria even have their own DNA termed mitochondrial DNA (mDNA) and can replicate.

Finally there is the controller of the cell. This is the nucleus. Not all cells have a nucleus and are termed anucleate. If you look at the image of the red blood cells you will see a white dot in the center of the cell – that is where the nucleus used to be. The nucleus is ejected when they mature. Some cells have more than one nucleus and are termed multinucleate. Skeletal muscle cells are very large cells and are multinucleate. The nucleus contains the DNA of the cell and the nucleolus. The nucleolus is an organelle that makes ribosomes. The DNA is your genetic code. It contains the genes that contain the instructions for making every protein in your body. The nucleus is surrounded by it’s own membrane with tiny holes termed nuclear pores. The membrane is called the nuclear membrane or nuclear envelope.

The interactive diagram below shows a drawing of a eukaryotic cell. The cell components in the list link to images that highlight these same structures in a living cell.

The cell membrane is a dynamic structure composed of lipids, proteins, and carbohydrates. It protects the cell by preventing materials from leaking out, controls what can enter or leave through the membrane, provides a binding site for hormones and other chemicals, and serves as an identification card for the immune system to distinguish between “self” and “non-self” cells. We will first investigate the anatomy of the cell membrane and then continue on to study the physiology of membrane transport.

The phospholipid bilayer is the main fabric of the membrane. The bilayer's structure causes the membrane to be semi-permeable. Remember that phospholipid molecules are amphiphilic, which means that they contain both a nonpolar and polar region. Phospholipids have a polar head (it contains a charged phosphate group) with two nonpolar hydrophobic fatty acid tails. The tails of the phospholipids face each other in the core of the membrane while each polar head lies on the outside and inside of the cell. Having the polar heads oriented toward the external and internal sides of the membrane attracts other polar molecules to the cell membrane. The hydrophobic core blocks the diffusion of hydrophilic ions and polar molecules. Small hydrophobic molecules and gases, which can dissolve in the membrane's core, cross it with ease.

Other molecules require proteins to transport them across the membrane. Proteins determine most of the membrane's specific functions. The plasma membrane and the membranes of the various organelles each have unique collections of proteins. For example, to date more than 50 kinds of proteins have been found in the plasma membrane of red blood cells.

The cell membrane is not a static structure. It is a dynamic structure that allows the movement of phospholipids and proteins. Fluidity is a term used to describe the ease of movement of molecules in the membrane and is an important characteristic for cell function. Fluidity is dependent on the temperature (increased temperatures it more fluid and decreased temperatures make it more solid), saturated fatty acids and unsaturated fatty acids. Saturated fatty acids make the membrane less fluid while unsaturated fatty acids make it more fluid. The correct ratio of saturated to unsaturated fatty acids keeps the membrane fluid at any temperature conducive to life. For example, winter wheat responds to decreasing temperatures by increasing the amount of unsaturated fatty acids in cell membranes to prevent the cell membrane from becoming too solid in the cold. In animal cells, cholesterol helps to prevent the packing of fatty acid tails and thus lowers the requirement of unsaturated fatty acids. This helps maintain the fluid nature of the cell membrane without it becoming too liquid at body temperature.

The fluidity of the membrane is demonstrated in the animation below. You will want to click the green arrow when the animation pauses to see all three parts. Select the magnifying glass to enlarge image.

Membranes also contain proteins, which carry out many of the functions of the membrane. Some functions of membrane proteins are:

• Transport. Because the plasma membrane is only semipermeable, the cell needs a way to transport larger materials into and out of the cell.
• Communication. Because the plasma membrane is the border of the cell, this is where the cell communicates with its environment. Membrane proteins are able to receive signals from outside the cell and begin a chain of events that cause the cell to respond to these signals.
• Metabolism. Membrane proteins can be enzymes that are involved in the chemical reactions of metabolism. These are the processes that allow the cell to grow, obtain energy, and eliminate wastes.
• Adhesion. Membrane proteins help cells bind to each other and form tissues. One example of this is skin cells, which must form a tight surface if the skin is to maintain proper integrity. Membrane proteins also bind to molecules inside and outside the cell which help the cell maintain its structure.

Membrane proteins are classified into two major categories: integral proteins and peripheral proteins. Integral membrane proteins are those proteins that are embedded in the lipid bilayer and are generally characterized by their solubility in nonpolar, hydrophobic solvents. Transmembrane proteins are examples of integral proteins with hydrophobic regions that completely span the hydrophobic interior of the membrane. The parts of the protein exposed to the interior and exterior of the cell are hydrophilic. Integral proteins can serve as pores that selectively allow ions or nutrients and wastes into or out of the cell. They can also transmit signals across the membrane.

Unlike integral proteins that span the membrane, peripheral proteins reside on only one side of the membrane and are often attached to integral proteins. Some peripheral proteins serve as anchor points for the cytoskeleton or extracellular fibers. Proteins are much larger than lipids and move more slowly. Some move in a seemingly directed manner, while others drift. Some are glycoproteins which have a carbohydrate group attached to the protein. These are on the outside of the membrane and important for cell recognition, they work like a cellular identification card.

The extracellular surface of the cell membrane is decorated with carbohydrate groups attached to lipids and proteins. Carbohydrates are added to lipids and proteins by a process called glycosylation, and are called glycolipids or glycoproteins. These short carbohydrates, or oligosaccharides, are usually chains of 15 or fewer sugar molecules. Oligosaccharides give a cell identity (i.e., distinguishing "self" from "nonself") and are the distinguishing factor in human blood types and transplant rejection.

Diffusion relies on kinetic energy and a concentration gradient. Kinetic energy is affected by temperature, size of molecules, steepness of the gradient, and the medium the molecules are in. Anything that increases the kinetic energy of the molecules will increase the rate of diffusion.

Diffusion is the movement of molecules from an area of high concentration to an area of lower concentration. There are different types of diffusion: simple in which the molecule passes directly through the phospholipid bilayer and facilitated which uses the integral membrane proteins as channels. Simple diffusion occurs when the molecules are either very small or lipid soluble and pass through the phospholipid bilayer of the cell membrane. Some examples of substances that use this process are oxygen (O₂), carbon dioxide (CO₂), and lipids.

The molecules will move from an area of high concentration down its diffusion (or concentration) gradient to the lower concentration until equilibrium is reached. Once the concentration is the same on both sides of the membrane, the molecules continue to move but they maintain the same levels at equilibrium.

Have you ever had the pleasant surprise of waking up to the smell of coffee or bacon? It’s the diffusion of the chemicals (odorants) moving from the higher concentration in your kitchen to you! In the human body the diffusion of O₂ and CO₂ are critical for gas exchange. O₂ levels are higher in your arterial blood than your tissue cells so O₂ will diffuse out of the blood into your cells. CO2 has the opposite concentration gradient. CO₂ levels are highest in your cells (your mitochondria produce CO2 as a waste product from cellular respiration) and CO₂ diffuses out of the cell into the blood. These molecules are small enough to pass through the phospholipid bilayer and are examples of simple diffusion. Remember that anything that increases kinetic energy will also increase the rate of diffusion.

The following animation depicts this simple diffusion process.

learn by doing

As three different molecules move, they encounter the lipid bilayer depicted by the horizontal membrane across the center of the stage in the preceding animation. Notice that one type of molecule passes freely through the lipid bilayer while the second type of molecule only occasionally passes through the membrane, and the lipid bilayer is totally impermeable to the third type of molecule.

The size, polarity, and charge of a substance will determine whether or not the substance can cross the cell membrane by diffusion. The cholesterol was an example of a lipid, and is highly soluble in the nonpolar environment of the lipid bilayer. You saw, in the animation above, the cholesterol freely passing into the hydrophobic environment of the membrane. The cholesterol distributes freely in the membrane and then some fraction will dissolve in the aqueous environment of the cytoplasm. Water, on the other hand, while polar, is small and because of this is able to freely cross the membrane. The lipid bilayer is much less permeable to the ion, because of its charge and larger size. As a general rule, charged molecules are much less permeable to the lipid bilayer.

Cells must be able to move large polar and charged molecules across the lipid bilayer of the membrane in order to carry out life processes. To allow these molecules, which are not soluble in the lipid bilayer, to pass across the hydrophobic barrier it is necessary to provide ports, channels or holes through the membrane. The molecules will still move spontaneously down a concentration gradient from high to low concentration. Some of these channels can remain open at all times, allowing the molecules to move freely according to the concentration gradient. Others can be gated channels that open and close in response to the needs of the cell. In most cases these channels are very discriminatory and will only allow specific molecules to pass. The process of moving impermeable molecules across a membrane (down their concentration gradients) using channels or pores is referred to as facilitated diffusion. Because the molecules are moving down a concentration gradient, the process is driven by simple diffusion and does not require the input of additional energy from the cell. The following simulation depicts the facilitated diffusion of glucose across the membrane using the glucose permease transporter.

Cells continually encounter changes in their external environment. Most cells have a similar blend of solutes within them, but interstitial or extracellular fluid can vary. What will happen if there is a strong concentration gradient between a cell's interior and the fluid outside? As you know, molecules will tend to move down their concentration gradients until equilibrium is reached. You might think that solutes will flow into our out of the cell until the solute concentrations are equal across the membrane. However, not all molecules can pass through the cell membrane. The plasma membrane (lipid bilayer) is significantly less permeable to most solutes than it is to water. Therefore the WATER tends to flow in a way that establishes an equal concentration of solutes on either side of the membrane. The water flows down its own concentration gradient, with a net movement toward the region that has a higher concentration of solutes. This movement of water across a semipermeable membrane in response to an imbalance of solute is called osmosis.

The relationship between the solute concentration and amount of water is an inverse relationship. The more concentrated a solution is, the less water it contains. The fewer solutes, the more water – i.e. it is more dilute. Water follows gradients and moves from an area of more water to less water but in reality water is moved to the area with the greater number of solutes. This creates a pressure termed osmotic pressure. Cells cannot actively move water, it must follow osmotic gradients. Solutions that have a greater solute concentration will pull water via osmotic pressure. This depends on the total number of solutes, not the type. Note that some water can pass through the cell membrane but most water passes through protein membrane channels termed aquaporins

Cells may find themselves in three different sorts of solutions. The terms isotonic, hypertonic, and hypotonic refer to the concentration of solutes outside the cell relative to the solute concentration inside the cell. In an isotonic solution, solutes and water are equally concentrated within and outside the cell. 0.9% NaCl (physiologic saline) and 5% dextrose are two common isotonic solutions used.The cell is bathed in a solution with a solute concentration that is similar to its own cytoplasm. Many medical preparations (saline solutions for nasal sprays, eye drops, and intravenous drugs) are designed to be isotonic to our cells. A hypotonic solution has a low solute concentration and a high concentration of water compared to the cell's cytoplasm. Distilled (pure) water is the ultimate hypotonic solution. If a cell is placed in a hypotonic solution, it will tend to gain water. The solutes will "stay put" within the cell, but water molecules will diffuse such that their net flow is toward the area with a higher concentration of solutes. A hypertonic solution has a high solute concentration (lower water concentration) compared to the cell cytoplasm. Very salty or sugary solutions (brines or syrups) are hypertonic to living cells. If a cell is placed in such a solution, water tends to flow spontaneously out of the cell.

Filtration is another passive process of moving material through a cell membrane. While diffusion and osmosis rely on concentration gradients, filtration uses a pressure gradient. Molecules will move from an area of higher pressure to an area of lower pressure. Filtration is non-specific. This means that it doesn’t sort the molecules, they pass due to pressure gradients and their size. If molecules are small enough to pass through the membrane, they will. The force that pushes the molecules is termed hydrostatic pressure.

Filtration is one of the main methods used for capillary exchange. Blood pressure provides the driving force or hydrostatic pressure to force materials out of capillaries to cells or to form the filtrate (fluid in the nephron of the kidney). Hydrostatic pressure is countered by osmotic pressure. Remember osmotic pressure is created due to increased solute concentration and will pull water toward the area of higher solutes. These two pressures must be in balance for homeostasis of fluid volumes. In our body large molecules such as plasma proteins and red blood cells should not pass out of the blood through the cell membranes lining the capillaries. If they pass through and end up in in the tissues or in the kidney and later the urine it is abnormal and a sign of disease.

You have just finished investigating the passive methods of transport, now let’s look at active methods. In active methods the cell must expend energy (ATP) to do the work of moving molecules. Active transport often occurs when the molecule is being moved against its concentration gradient or when moving very large molecules into our out of the cell. There are 3 main types of active processes.

1. Primary Active Transport or Solute Pumps
2. Endocytosis and Exocytosis

Another form of active transport is termed secondary active transport. While primary active transport directly uses ATP, secondary active transport relies on the energy from electrochemical gradients to move molecules against their gradients. Primary active transport sets this up because it actively pumps ions such as Na⁺ out of the cell thereby creating an electrochemical gradient for Na⁺ across the cell membrane. Protein transporters in the cell membrane use the energy from electrochemical gradients to transport molecules. If the molecules move in the same direction this is known as cotransport or symport. If they are moved in opposite directions this is known as countertransport or antiport. One common occurrence in the human body is the Na⁺/glucose transport protein known as SGLT1 which cotransports 1 glucose and 2 sodium ions into a cell. The electrochemical gradient for Na⁺ into the cell allows glucose to ride with it. When glucose moves into a cell, it rides the energy from the “coat tails of sodium ions”.

Facilitated diffusion and active transport are not the only ways that materials can enter or leave cells. Through the processes of endocytosis and exocytosis, materials can be taken up or ejected in bulk, without passing through the cell's plasma membrane.

In endocytosis, material is engulfed within an infolding of the plasma membrane and then brought into the cell within a cytoplasmic vesicle. To begin endocytosis, a particle encounters the cell surface and produces a dimple or pit in the membrane. The pit deepens, invaginates further, and finally pinches off to form a vesicle in the cytoplasm of the cell. Note that during the process the inside surface of the newly formed vesicle is the same as the exterior surface of the cell. Thus the integrity of the cytoplasm and the orientation of the plasma membrane are preserved. Once internalized, this new vesicle containing extracellular materials may fuse with a lysosome so that its solid contents are digested. The resulting molecules may be released to the cytoplasm for use within the cell.

There are two general forms of endocytosis: phagocytosis and pinocytosis. Phagocytosis is the uptake of large solid particles such as bacteria or cellular debris. Pinocytosis is the uptake of fluid and any small molecules dissolved within it. Cells are also capable of recognizing specific particles and engulfing them in a more targeted way, a process called receptor-mediated endocytosis. In this case, the particle first binds to a membrane protein receptor on the surface of the cell. Binding of the target particle induces the cell to engulf it.

Exocytosis is just the reverse of endocytosis. In exocytosis, an internal vesicle fuses with the plasma membrane and releases its contents to the outside. The balance of exocytosis and endocytosis preserves the size of the plasma membrane and keeps the cell's size constant. The following animation depicts endocytosis.

How are endocytosis and exocytosis important to everyday life? Immune cells protect animals by recognizing and destroying foreign objects such as bacteria. Disease-causing bacteria are recognized by proteins called receptors on the surface of the immune cell. The phagocytic immune cell will then engulf the bacterial cells (phagocytosis). The vesicle that contains these bacterial cells is called a phagosome ("phago" means "eating" and "-some" refers to "body"). The phagosome next fuses with lysosomes. Finally, the digested bacterial products are excreted through the process of exocytosis.

Phagocytosis of a Bacterium

Even though we may not feel any changes from day to day, we are constantly repairing and replacing cells within our bodies. It’s estimated that approximately 300 million cells die every minute in our body! These cells must be replaced by identical functional cells for us to survive and maintain homeostasis. The process of cell proliferation or cell division is termed mitosis. Mitosis produces two daughter cells that are identical (clones) to the parent cell.

Cell division is a carefully regulated process. There are “check-points” between phases, in which the cell “self-checks.” Through molecular interactions, the cell makes sure that it is ready to divide; for example, it checks to see that its DNA has not been damaged. If all criteria are met, the cell moves forward through the cell cycle. Normal cells usually divide only a limited number of times, and usually do so when stimulated by certain molecular signals. For example, if you move to higher altitude, your body will produce more red blood cells in order to supply enough oxygen despite the thinner air.

Mitosis is also regulated by genes. Some genes become active to stimulate mitosis and other genes act as the brakes to turn it off (suppressor genes). If our body loses control over mitosis the result would be the production of too many (hyperplasia) abnormal cells and would form a tumor. If the tumor is encapsulated it is termed benign. If not, the mutated cells can spread and it is known as cancer. Cancer cells, on the other hand, have lost the normal cell cycle controls, and therefore can divide indefinitely.

When a cell is performing its normal day-to-day functions it is in a state termed interphase. When it is time for that cell to replicate, genes become active and stimulate it to begin mitosis. Mitosis is characterized by four phases. Remember if a cell is going to form 2 new identical cells it must first replicate it’s DNA and organelles. It is during interphase that the DNA is replicated to form 2 identical strands. These strands of identical DNA are termed chromatids and are held together with a centromere.

The stages of mitosis occur in sequence with specific events in each one. It is only during mitosis that chromosomes are visible. Usually DNA is in its threadlike chromatin form. You can identify the stages of mitosis by observing the chromosomes. Remember that the DNA is in the nucleus which is surrounded by the nuclear membrane. The DNA needs to be free from the nucleus so it can be evenly distributed to two daughter cells. The events of mitosis describe the processes of splitting and moving nuclear DNA to opposite ends of the parent cell where the nuclear membranes will reform. Then the cell membrane can split the cytoplasm and organelles (termed cytokinesis). The two daughter cells will each have the same genetic code. When you studied the cell you learned about the microtubules of the centrioles. They are the organelles that will move the DNA during mitosis.

The major stages of mitosis are:

1. Prophase
2. Metaphase
3. Anaphase
4. Telophase

In the body's organizational hierarchy, tissues occupy a place between cells and organs. That is, a tissue is a group of cells with a similar shape and function. In turn, organs (which make up the body) are comprised of various tissues.

The component cells of a tissue are a specific cell type. A tissue’s cells may be identical, but are not necessarily so. Several tissues will comprise an organ. For example, the contractile cells of skeletal muscle are bundled together to make muscle fiber tissue. In turn, endomysium cells form enclosing tissue that wraps around bundles of muscle fibers, like a tortilla around the filling of a burrito. Several of these structures are in turn wrapped by another tissue, perimysium. Finally, bundles of these are surrounded by a sheath of yet another tissue, epimysium, which covers the outside of the whole muscle. Yet more tissue is necessary for the muscle to function in the body. Connective tissue comprising ligaments attaches the muscle to the skeleton, and nerve tissue conducts impulses from the nervous system to signal the muscle to contract.

Skeletal muscle is only one kind of tissue. The body is made of dozens of different tissues, but broadly speaking there are four types of tissues.

• Muscle tissue (in turn divided into skeletal, smooth and cardiac) is contractile. It allows locomotion of the body. It also allows necessary contractions of various organs such as the heart and of respiratory and digestive systems.
• Nerve tissue comprises the body’s wiring system. It conducts signals between the nervous system and various organs.
• Connective tissue holds the body together. It is found in most organs, anchoring them to the skeleton and other organs. Types of connective tissue include fibrous tissue, fatty tissue, loose tissue and cartilage. Connective tissue also includes bone, blood and lymph.
• Epithelial tissue is the body’s protection against the outside environment. Skin tissue helps to maintain homeostasis. It helps monitor and control temperature, and resists abrasion, foreign bodies and damaging chemicals. Internally, epithelial tissue lines most internal cavities, secreting or absorbing nutrients.

Tissues form during development. Stem cells in the embryo differentiate into various cell types. The necessary genes in the cells turn on or off, resulting in the production of proteins that characterize a cell’s structure and function. Early in embryonic growth, the cells migrate to the appropriate location in the body. Once there, they proliferate so that the tissue can perform its needed function.

Different tissues arise from the source cells in each of the three primary germ cell layers. For example, the epithelium is derived from the ectoderm and endoderm. Connective tissue arises largely from the mesoderm. Gastrointestinal and respiratory tissues arise mostly from the endoderm. Programmed cell death, or apoptosis, may take place to eliminate transitory tissues in the embryo, such as the pronephros, a simple excretory organ that is later replaced by the kidney.

The organ level of organization in the body may be the most familiar to us from our everyday experiences. Many of the common ailments we hear about—an upset stomach, a broken bone, lung disease, skin cancer—are named for the organs they affect.

An organ is made up of tissues that work together to perform a specific function for the body as a whole. Groups of organs that perform related functions are organized into organ systems, which perform more general functions. The table below describes the structures and functions of some common organs.

Organ systems are made up of organs that work together to perform a specific function for the body as a whole. The table below describes the organ systems and their primary organs and physiological functions.

The maintenance of homeostasis in the body requires feedback loops that control the body's internal conditions. We use the following terminology to describe feedback loops:

• Variables are parameters that are controlled or affected by the feedback system.
• Receptors detect changes in the variable.
• Control centers (integrators) compare the variable in relation to a set point and signal the effector to generate a corrective response.
• Effectors execute the necessary changes to adjust the variable.

Example

Terms applied to temperature

Consider one of the feedback loops that controls body temperature.

• Variable

  In this instance, the variable is body temperature.

• Receptors

  Thermoreceptors detect changes in body temperature. For example, thermoreceptors in your internal organs can detect a lowered body temperature and produce nerve impulses that travel to the control center, the hypothalamus.

• Control Center

  The hypothalamus controls a variety of effectors that respond to a decrease in body temperature.

• Effectors

  There are several effectors controlled by the hypothalamus.

  • blood vessels near the skin constrict, reducing blood flow (and the resultant heat loss) to the skin.
  • Skeletal muscles are also effectors in this feedback loop: they contract rapidly in response to a decrease in body temperature. This shivering helps to generate heat, which increases body temperature.

did I get this

Remember that homeostasis is the maintenance of a relatively stable internal environment. When a stimulus, or change in the environment, is present, feedback loops respond to keep systems functioning near a set point, or ideal level.

Typically, we divide feedback loops into two main types:

• positive feedback loops, in which a change in a given direction causes additional change in the same direction.
  • For example, an increase in the concentration of a substance causes feedback that produces continued increases in concentration.
• negative feedback loops, in which a change in a given direction causes change in the opposite direction.
  • For example, an increase in the concentration of a substance causes feedback that ultimately causes the concentration of the substance to decrease.

Positive feedback loops are inherently unstable systems. Because a change in an input causes responses that produce continued changes in the same direction, positive feedback loops can lead to runaway conditions. Some positive feedback loops can be harmful. However, there are a few instances in which positive feedback helps to maintain homeostasis. One such example is blood clotting. When a blood vessel is broken, a clot begins to form and clotting factors are activated at the site. The activation of clotting factors continues into a chain reaction until bleeding within the vessel stops. In this instance, the set point is the point at which no blood leaves the site. The release of clotting factors stimulates further release of clotting factors, until the blood is so heavily clotted that no blood leaves the vessels. Some positive feedback loops are part of normal physiology. Some endocrine and reproductive functions, particularly in women, are part of positive feedback loops.

Negative feedback loops are inherently stable systems. Negative feedback loops typically produce conditions that oscillate around the set point. For example, negative feedback loops involving insulin and glucagon help to keep blood glucose levels within a narrow range of concentrations. If glucose levels get too high, the body releases insulin into the bloodstream. Insulin causes the body's cells to take in and store glucose, lowering the blood glucose concentration. If blood glucose gets too low, the body releases glucagon, which causes the release of glucose from the body's cells.

In a positive feedback mechanism, the output of the system stimulates the system in such a way as to further increase the output. Common terms that could describe positive feedback loops include "snowballing" and "chain reaction". Without a counter-balancing or "shut-down" reaction or process, a positive feedback mechanism has the potential to produce a runaway process. Some physiological processes mediated by positive feedback help maintain homeostasis. In these cases, the positive feedback loop always ends with counter-signaling that suppresses the original stimulus.

Example

Blood clotting

Because of its ability to generate an amplifying process, beneficial positive feedback is often seen where a rapid response is needed. For example, blood clotting (or coagulation) starts with a wound that causes release of blood from damaged blood vessels. When the lining of the blood vessels (endothelium) is ruptured, proteins in the lining are exposed to collagen and other clotting factors. Platelets (small cell fragments) in the blood stick to the edges of the blood vessels and form an initial clot to plug the wound.

After they stick to the damaged blood vessels, the platelets release granules. The granules contain additional stimulatory molecules including serotonin, adenosine diphosphate (ADP), and thromboxane. The ADP attracts other platelets to the wound site. When they arrive, the thromboxane prompts them to aggregate and to release more granules in turn. The ADP and thromboxane thus promote the release of more ADP and more thromboxane in a positive feedback cascade. The result is a platelet plug that closes the wound.

Following this first line of defense, multiple proteins called clotting factors act together in a coagulation cascade to form a secondary clot. Once the bleeding stops, the stimuli promoting clotting processes are no longer present, so the cascading processes cease.

Example

Heart failure

The above provide examples of beneficial positive feedback mechanisms. However, in many instances, positive feedback can be potentially damaging to life processes. For example, a myocardial infarction (heart attack) begins when a small portion of heart tissue dies off (usually due to inadequate blood supply). The loss of tissue then results in too little blood being pumped to the body tissues and cardiac muscle tissue, so the heart must work harder and more heart tissue can become damaged and decrease heart function further.

Most biological feedback systems are negative feedback systems. Negative feedback occurs when a system's output acts to reduce or dampen the processes that lead to the output of that system, resulting in less output. In general, negative feedback loops allow systems to self-stabilize.

Example

Insulin

An important example is the control of blood sugar levels following a meal.

1. After a meal, the small intestine absorbs glucose from digested food. Blood glucose levels rise.
2. Increased blood glucose levels stimulate beta cells in the pancreas to produce insulin.
3. Insulin triggers liver, muscle, and fat tissue cells to absorb glucose, where it is stored. As glucose is absorbed, blood glucose levels fall.
4. Once glucose levels drop below a threshold, there is no longer a sufficient stimulus for insulin release, and the beta cells stop releasing insulin.

Due to synchronization of insulin release among the beta cells, basal insulin concentration oscillates in the blood following a meal. The oscillations are clinically important, since they are believed to help maintain sensitivity of insulin receptors in target cells. This loss of sensitivity is the basis for insulin resistance. Thus, failure of the negative feedback mechanism can result in high blood glucose levels, which have a variety of negative health effects.

Example

Temperature

Negative feedback is a vital control mechanism for the body’s homeostasis. One important example of how a negative feedback loop maintains homeostasis is the body’s thermoregulation mechanism. The body maintains a relatively constant internal temperature to optimize chemical processes. The hypothalamus, located in the brain, monitors body temperature. Neural impulses from heat-sensitive thermoreceptors in the skin signal the hypothalamus. As skin temperature rises, the hypothalamus initiates release of water (sweat) from sweat glands. Evaporation cools the skin until its temperature returns to normal. Once its temperature returns to normal, the thermoreceptors in the skin cease to signal the hypothalamus, and sweating stops. Likewise, when body temperature drops, the hypothalamus initiates several physiological responses to increase heat production and conserve heat:

• Narrowing of surface blood vessels (vasoconstriction) decreases the flow of heat to the skin.
• Shivering commences, increasing production of heat by the muscles.
• Adrenal glands secrete stimulatory hormones such as norepinephrine and epinephrine to increase metabolic rates and hence heat production.

These effects cause body temperature to increase. When it returns to normal, the hypothalamus is no longer stimulated, and these effects cease.

Let's take a closer look at diabetes. In particular, we will discuss diabetes type 1 and type 2. Diabetes can be caused by too little insulin, resistance to insulin, or both.

Diabetes Type 1 is usually diagnosed in childhood. However, many patients are diagnosed when they are older than age 20. In this disease, the body makes little or no insulin. Daily injections of insulin are needed. The exact cause is unknown. Genetics, viruses, and autoimmune problems may play a role.

Also affected are those who lose their pancreas. Once the pancreas has been removed (because of cancer, for example), diabetes type 1 is always present.

Diabetes Type 2 is far more common than type 1. It makes up most of diabetes cases. It usually occurs in adulthood, but young people are increasingly being diagnosed with this disease. The pancreas does not make enough insulin to keep blood glucose levels normal, often because the body does not respond well to insulin. Many people with type 2 diabetes do not know they have it, although it is a serious condition. Type 2 diabetes is becoming more common due to increasing obesity and failure to exercise.

You have read about general and specific examples of homeostasis, including positive and negative feedback loops, and have learned the terminology that is used to describe parts of the feedback loops. It is important to become comfortable with the terminology, since it will be used to introduce new concepts in upcoming sections of this course.

Maintaining homeostasis within the body is important for proper physiological function, growth and remodeling. It is important to recognize the mechanisms of homeostasis in the body, as well as the consequences of homeostasis dysfunction.

In the following examples, you will learn to identify homeostasis at different levels of organization, such as how the body maintains tight control over small molecules, and the importance of maintaining cell number with regard to tissue homeostasis.

Body functions such as regulation of the heartbeat, contraction of muscles, activation of enzymes, and cellular communication require tightly regulated calcium levels. Normally, we get a lot of calcium from our diet. The small intestine absorbs calcium from digested food.

The endocrine system is the control center for regulating blood calcium homeostasis. The parathyroid and thyroid glands contain receptors that respond to levels of calcium in the blood. In this feedback system, blood calcium level is the variable, because it changes in response to the environment. Changes in blood calcium level have the following effects:

• When blood calcium is low, the parathyroid gland secretes parathyroid hormone . This hormone causes effector organs (the kidneys and bones) to respond to increase calcium levels. The kidneys prevent calcium from being excreted in the urine. Osteoclasts in bones reabsorb bone tissue and release calcium.
• When blood calcium levels are high, the thyroid gland releases calcitonin .Calcitonin causes the kidneys to reabsorb less calcium from the filtrate, allowing excess calcium to be removed from the body in urine. Calcitonin also suppresses the formation of active vitamin D in the kidneys; without vitamin D the small intestines don't absorb as much dietary calcium. Osteoblasts, stimulated by calcitonin, use calcium in the blood to add to bone tissue.

Calcium imbalance in the blood can lead to disease or even death. Hypocalcemia refers to low blood calcium levels. Signs of hypocalcemia include muscle spasms and heart malfunctions. Hypercalcemia occurs when blood calcium levels are higher than normal. Hypercalcemia can also cause heart malfunction as well as muscle weakness and kidney stones.

Glucose is an important energy source used by most cells in the body, especially muscles. Without glucose, the body "starves," but if there is too much glucose, problems occur in the kidneys, eyes, and even with the immune response. Insulin, a hormone produced by the pancreas in response to increased blood glucose levels. When the pancreas releases insulin, it acts as a key to open glucose passageways to enter cells. Glucose enters the cells where it is used for energy production. Excess glucose is used to synthesize glycogen for storage. The pancreas also produces the hormone glucagon. Glucagon is released with blood glucose levels decrease and breaks down glycogen back to glucose which is released into the blood to bring blood glucose levels back up.

Tissues have an optimal number of cells for function. Cells are able to interact with their neighbors using cell-to-cell connections or cell-to-cell signaling to maintain homeostasis of cell number. Normally cells will stop dividing when there is an appropriate number of cells in a tissue or space. If a neighboring cell is lost or if there is an inadequate number of cells, cells may be stimulated to divide. Cells with too many neighbors trigger an internal response to die in a regulated programmed way called apoptosis. When cells sense they have no neighbors, signals in the nucleus cause division of the cell.

Each organ system performs specific functions for the body, and each organ system is typically studied independently. However, the organ systems also work together to help the body maintain homeostasis.

As you have learned, proper calcium levels are important to maintain whole body homeostasis. Calcium ions are used for the heartbeat, the contraction of muscles, the activation of enzymes, and cellular communication. The parathyroid and thyroid glands of the endocrine system detect changes in blood calcium levels. When the parathyroid glands detect low blood calcium levels, several organ systems alter their function to restore blood calcium levels back to normal. The skeletal, urinary, and digestive systems all act as effectors to achieve this goal through negative feedback.

The release of parathyroid hormone from the endocrine system triggers osteoclasts of the skeletal system to resorb bone and release calcium into the blood. Similarly, this hormone causes the kidneys of the urinary system to reabsorb calcium and return it to the blood instead of excreting calcium into the urine. Through altered function of the kidneys to form active vitamin D, the small intestine of the digestive system increases the absorption of calcium.

When the thyroid gland detects elevated blood calcium levels, the skeletal, urinary, and digestive systems contribute to lower blood calcium levels back to normal. Release of the hormone calcitonin from the thyroid gland of the endocrine system triggers a series of responses. The osteoblasts of the skeletal system use excess calcium in the blood to deposit new bone. The kidneys of the urinary system excrete excess calcium into the urine instead of reclaiming calcium through reabsorption. Lastly, the kidneys stop forming active vitamin D, which causes decreased intestinal absorption of calcium through the digestive system.

The endocrine functions of the pancreas and liver coordinate efforts to maintain normal blood glucose levels. When pancreatic cells detect low blood glucose levels, the pancreas synthesizes and secretes the hormone glucagon. Glucagon causes the liver to convert the polymerized sugar glycogen into glucose through a process known as glycogenolysis. Glucose then travels through the blood to allow all cells of the body to use it.

If pancreatic cells detect high blood glucose levels, the pancreas synthesizes and releases the hormone insulin. Insulin causes polymerization of glucose into glycogen, which is then stored in the liver through a process known as glycogenesis.

The nervous and digestive systems also play a role in maintaining blood glucose levels. When the stomach is empty and blood glucose levels are low, the digestive system and the brain respond by making you feel hungry—your stomach may "growl," and you may feel pain or discomfort in your midsection. These sensations prompt you to eat, which raises blood glucose levels.

All organ systems require a balance of cell division and apoptosis during development, growth, and repair to maintain tissue structure and function. The endocrine and immune systems are important regulators for cell populations. The endocrine system delivers steroids and growth hormones that send survival signals to specific tissues so that apoptosis is prevented. Additionally, the endocrine system delivers some hormones that work to induce apoptosis under some physiological conditions.

The cells of the immune system screen the blood for cells that divide at inappropriate times. Immune cells produce antibodies to mark these out-of-control cells for destruction. A breakdown in these processes can lead to the formation of tumors.

Like all body systems, the skeletal system can be affected by disease and injury. By studying the responses of the skeletal system to these conditions, we can learn about how the components of the skeletal system interact and how the skeletal system interacts with the rest of the body. We will consider six common dysfunctions of the skeletal system:

• Fractures: Breakage of the solid bones.
• Osteoarthritis: a chronic inflammation and damage of the articular cartilage.
• Osteogenesis imperfecta: A genetic condition leading to small bones.
• Osteomalacia ("rickets"): A bone disorder caused by a lack of vitamin D.
• Osteoporosis: A bone weakening condition, most common in women, caused by hormonal changes.
• Rheumatoid arthritis: An autoimmune disease that can damage the articular cartilage.

While the skeletal system primarily supports the body and allows movement, it also performs a variety of important functions and impacts many other organ systems.

It's common to think of the skeletal system as being made up of only bones, but the skeletal system contains many types of structures. In addition to localizing blood cell formation and storing calcium, bones come together at locations called articulations (or joints) to allow for locomotion and work. In any complex system that moves (such as a bicycle or car), allowing functional, repetitive motion requires a lot of control and support.

Connective Tissues

In addition to bones, the skeletal system contains several other important connective tissues: cartilage , ligaments , and tendons .

Cartilage is a firm yet pliable substance that performs a variety of functions: protection, shape maintenance and support, lubrication, and shock absorption. Its primary function is to coat the end of the bones where they articulate with one another, providing a smooth, cushioned surface. Furthermore, cartilage can serve as a template for bone formation during development and bone healing (this will be further discussed in the section about bone homeostasis).

Ligaments and tendons support articulations and control the muscle attachment to the bones. Ligaments connect bones to one another and stabilize articulations. Tendons connect bones to muscles.

The structures of ligaments and tendons are similar, in that both tissues are made of fibrous proteins aligned in the direction of force. The types of proteins and differences in stretch and recoil distinguish the mechanical behavior of ligaments and tendons. Ligaments are stiffer, but deform more, since they stabilize articulations. Tendons are wrapped with a continuation of the fascia that surrounds muscle cells to help transmit and dissipate force.

The adult human skeletal system is composed of 206 bones. The skeleton is divided into two functional groupings—the axial skeleton and the appendicular skeleton .

The Axial Skeleton

The axial skeleton is composed of the skull, hyoid bone, vertebral column, and the thorax (ribs and sternum). The axial skeleton functions to protect and support organs of the head, neck, and trunk.

The skull consists of 22 facial and cranial bones that interlock to form openings for the eyes and protection for the brain. The cranium, a collection of bones that protect the brain, and the mandible are the two major parts of the skull.

The hyoid bone is not attached to any other bone and is located in the neck, and it supports tongue movement.

The vertebral column consists of individual vertebrae separated by cartilage disks. The vertebral column forms the middle axis of the skeleton.

The thoracic cage protects the internal organs of the upper abdomen. The thoracic cage consists of the ribs and the sternum. The ribs articulate anteriorly with the sternum and posteriorly with the vertebrae of the thorax.

The table below lists the location and function of the major bones of the axial skeleton:

Bone(s)	Location	Function	Major grouping of axial skeleton
Cranium	Head	Supports facial structures, encloses and protects the brain, provides muscle attachments for chewing and moving the head	Skull
Mandible	Lower jaw	Permits chewing	Skull
Vertebrae	Spine	Permit mechanical stability for the body and protect the spinal cord	Vertebral column
Ribs	Chest wall	Provide protection for the organs of the upper body	Thoracic cage
Sternum	Center of the chest	Provides attachment for many (not all) ribs	Thoracic cage

The appendicular skeleton is composed of the upper limbs, lower limbs, pectoral girdle, and pelvic girdle. The appendicular skeleton functions to anchor the limbs to the axial skeleton.

The pectoral girdle consists of a scapula and clavicle on each side of the body. The pectoral (shoulder) girdle permits movement of the upper limbs by connecting the upper limbs to the axial skeleton.

The upper limbs of the appendicular skeleton are composed of the humerus or upper arm bone, the radius and ulna, which complement each other to form the forearm, and the wrist. The hand subdivides into smaller bones of the palm and fingers.

The pelvic girdle of the appendicular skeleton is composed of two coxal bones (fused ilium, ischium and pubis bones), which attach to the vertebral column and the lower limbs.

The lower limbs each consist of the femur, or thigh bone; the tibia, or shinbone and the fibula, or calf bone; and the foot. The patella is the bone located at the point where the femur and tibia articulate with each other. The foot subdivides into smaller bones of the ankle, instep, and toes.

The table below lists the location and function of the major bones of the appendicular skeleton:

The bones of your body are mineralized structures that make up a major portion of your skeleton. In the broad sense, a bone is composed of bone tissue, cartilage, ligaments, tendons, vasculature, and nervous tissue. Bone tissue is a collection of specialized cells (osteoblasts, osteoclasts, osteocytes), organic extracellular matrix proteins (collagen and proteoglycans) and inorganic salt crystals that work together to provide strength and flexibility.

Although all bones have a similar composition, their large-scale structures and functions differ. One way to classify bone tissue is based on their microscopic structure.

• Bone tissue with a tightly packed microstructure arranged into rings is called compact bone (also called cortical or lamellar bone). Compact bone structure gives bones their stiffness. However, if bone structures were made only of compact bone, they would be very heavy and brittle.
• Bone tissue with a porous microstructure is spongy bone (also called cancellous or trabecular bone). Spongy bone consists of branching bone structures called trabeculae . Spongy bone helps to reduce the weight and brittleness of bone, and is found at the ends of bone where forces are high. Spongy bone allows bones to bend a slight amount without cracking.

Most bones of the body are composed of both spongy and compact bone tissues, so that they are stiff, resilient and lightweight.

A common way to classify individual bones of the skeletal system is based on their shapes. The table below describes the four main shapes of bones.

Components of Long Bones

A typical long bone, such as the femur, has three main components:

• the diaphysis or shaft;
• the epiphyses (singular, epiphysis ), found at the bone ends;
• and the metaphyses (singular, metaphysis), transitional areas between the diaphysis and epiphyses.

Components of long bones. This work by Cenveo is licensed under a Creative Commons Attribution 3.0 United States (http://creativecommons.org/licenses/by/3.0/us/).

The diaphysis or shaft is the longest part of a long bone. The epiphyses (epiphysis if singular) are the ends of a long bone that articulate (connect) with other bones at articulations or joints. The transitional area between the diaphysis and epiphysis is the metaphysis (meta- means "in between"). The medullary cavity, which houses yellow bone marrow, begins at the boundary between the metaphysis and diaphysis of each bone end and runs throughout the shaft or diaphysis of the bone. This marrow is rich in fat which is why it is termed yellow bone marrow. The epiphyses contain mainly spongy (cancellous) bone and red bone marrow. In children, the junction between the epiphysis and metaphysis contains a layer of hyaline cartilage,termed the epiphyseal plate. You have most probably heard of this as the growth plate. This layer of cartilage is what allows bone to continue to lengthen. The cartilage cells undero mitosis and move away from the center of the bone toward the epiphyses while the bone grows into it and takes over. In adult bone, this cartilage has become calcified and hard, the bone has caught up and replaced all of the cartilage with bone. Now this area is termed the epiphyseal line. The only area of hyaline cartilage left is on the outer edge of each epiphysis. This cartilage is termed articular cartilage and functions to cushion and reduce friction between bones at articulations.

We can also use a bone's location within the axial or appendicular skeleton to classify it. In addition to classifying bones based on their shape, we divide the skeleton into axial and appendicular segments. The axial skeleton is composed of the skull, the hyoid bone in the throat, the vertebral column, and the thoracic cage. The appendicular skeleton is composed of the upper limbs, lower limbs, pectoral girdle, and pelvic girdle.

learn by doing

It's common to think of the skeletal system as being made up of only bones, and performing only the function of supporting the body. However, the skeletal system also contains other structures, and performs a variety of functions for the body.

While the bones of the skeletal system are fascinating, it is our ability to move segments of the skeleton in relation to one another that allows us to move around. Each connection of bones is called an articulation or a joint. Articulations are classified based on material at the joint and the movement allowed at the joint.

Synarthrosis Articulations

Immovable articulations are synarthrosis articulations ("syn" means together and "arthrosis" means joint); immovable articulations sounds like a contradiction, but all regions where bones come together are called articulations, so there are articulations that don't move, including in the skull, where bones have fused, and where your teeth meet your jaw. Synarthroses are often joined with fibrous connective tissue.

Amphiarthrosis Articulations

There are some articulations which have limited motion called amphiarthrosis articulations, that are held in place with cartilage or ligaments. Some amphiarthroses are permanent such as the articulation between the ribs and the sternum (via costal cartilage). Some are temporary such as the epiphyseal plate. Ribs connected to the sternum (except the first rib) and the two parallel bones in the arms and legs are considered amphiarthrosis articulations.

The articulations that people are most familiar with are diarthrosis articulations, which have wide ranges of motion. Diarthrotic articulations are said to be freely moveable and have a joint cavity. A joint cavity is a structure that consists of a joint capsule which surrounds the joint, and a synovial membrane which is inside the joint and produces a fluid known as synovial fluid. These joints are known as synovial joints and are further classified according to the type of movement allowed at the joint.

Nonaxial Joints

Nonaxial joints do not have a pivot or axis of movement. An example are gliding joints, also known as plane joints. These joints do not allow much movement other than sliding and twisting. These are often found in certain articulations in the wrist and ankle.

Gliding joint of the wrist

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Uniaxial or Monoaxial Joints

These joints have one axis of movement and are more moveable than gliding joints. Examples of uniaxial joints are hinge and pivot joints.

These joints have protrusions that fit into a corresponding depression; hinge joints, such as the elbow, allow the movement of flexion and extension. The pivot joint of the atlanto-axial joint (the atlas or C-1 on the axis or C-2) rotation of the head and neck. For example, when you shake your head "no" you are using this joint to rotate your head.

Elbow joint

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Cross section of vertabra

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Biaxial Joints

Biaxial joints have two axes of movement and therefore allow more movements than uniaxial joints. One example of a biaxial joint are saddle joints, such as the thumb. These joints were appropriately named because they look like saddles; there are two curved surfaces that meet and allow limited motion in many directions.

thumb joint

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Another example of a biaxial joint is an ellipsoid or condlyar joint. Ellipsoid articulations, also called condyloid articulations, have oddly shaped or elliptical interactions that articulate to allow movement in two planes with no rotation. These are present in the fingers and toes.

Finger joints

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Triaxial Joints

As you can guess, triaxial joints are the most moveable with three axes of movement. The ball and socket joints such as the shoulder and hip, have the widest range of motion. They are aptly named as the head of the bone resembles a "ball" and the articulating bone of the joint (either the scapula or coxal bone) has a deep pit for the "socket".

Hip joint

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The skeletal system is organized into the following structural hierarchy, from microstructure to gross anatomy:

• Chemistry and molecular scale - Water, minerals, collagen, and other proteins.
• Nanoscale - Mineral crystals are embedded within collagen to form composite fibers.
• Submicron scale - Mineralized fibrils are organized into a lamella (plural is "lamellae").
• Micron (micrometer) scale - Lamellae form osteons in compact bone or trabeculae in spongy bone.
• Macroscale - Compact and spongy bone combine together to form whole bones, and bones combine at articulations to form the skeletal system.

Bones constantly store and release calcium, phosphate, proteins, and other matrix components of bone. Within the matrix, the mineral crystals resist compression but are very brittle. The organic components, such as the collagen fibers and the cells, help give the bone some flexibility. The hierarchical organization of the skeletal system at different scales is important for its mechanical, biological, and chemical functions.

The major components of bone tissue at the molecular scale are minerals, water, collagen, and other proteins. At the next level of organization, small crystals of hydroxyapatite made of calcium and phosphate are embedded within collagen fibers to produce a composite (blended) material with high compressive and tensile strength.

The skeletal system protects and supports vital organs, allows our body to move, stores important minerals, and produces blood cells. There are several chemical elements and molecules required to maintain the many functions of the skeletal system. The chemical properties of these components support bone structure and function. On a chemical level, bone is divided into inorganic and organic (carbon-containing) components.

The primary inorganic components of bone are:

• calcium, which is required for many functions throughout the body;
• phosphorus (in the form of phosphate ions), which is a component of buffer systems and energy-rich molecules; and
• water, which contributes to the compressive resistance of bone and contributes to the fluid matrix of bone.

The primary organic components of bone are:

• collagen, the major structural protein (type I in bone and type II in cartilage); and
• proteoglycans , which are negatively charged glycosylated proteins (glycosylated means having carbohydrate sugar groups modifying the protein).

Bone is approximately 60 to 70 percent inorganic mineral and 10 percent water by weight. The remaining 20 to 30 percent of bone is organic matrix (osteoid), such as collagen and proteoglycans. Your body contains 1 to 2 kilograms of calcium and nearly 600 grams of phosphorous. Nearly 99 percent of the calcium and 86 percent of the phosphorous is stored in your bones.

Calcium ions (Ca²⁺) are stored in bone tissue, but can be released into the bloodstream when blood levels fall below optimal. Blood calcium is important for muscle contractions, nerve impulses, and blood clotting.

In bone, phosphorous (P) is found in the form of phosphate ions (H₂PO₄^-). Outside of bone, phosphorous plays roles in energy storage (such as in ATP), and is required for the formation of DNA and RNA. Therefore, it is required for cellular growth, maintenance, and tissue repair.

When combined with hydrogen, phosphorous forms dihydrogen phosphate ions (H₂PO₄^-). Dihydrogen phosphate acts as a buffer to maintain a constant pH balance by acting as either a hydrogen ion donor (acid) or a hydrogen ion acceptor (base). In all cells, a constant pH must be maintained to carry out cell functions.

As mentioned in previous sections, hydroxyapatite is an inorganic calcium phosphate mineral that is a primary component of bone. Crystal hydroxyapatite has the chemical formula: Ca₁₀(PO₄)₆(OH)₂.

During bone formation, the collagen fiber matrix is formed. Next, mineralization of the matrix occurs when calcium, phosphate, and water from the extracellular fluids combine to form insoluble hydroxyapatite. The hydroxyapatite incorporates into the small pores within collagen fibrils and crystallizes into long, thin, nanosized plates within the collagen network. The incorporation of hydroxyapatite within the collagen fibers contributes to the overall compressive strength of bone. Because the crystals are nanosized, they have a large surface area. The large surface area of the crystals makes it easy to release ions into the extracellular fluids when blood levels decrease.

Sometimes bones contain fluoride. Fluoride is similar to the hydroxyl ion in charge and size. When fluoride replaces the hydroxyl ion in hydroxyapatite crystals, it forms fluoroapatite. Fluoroapatite is a more compact and less soluble crystal than hydroxyapatite. Therefore, ion exchange at the crystal surface is slower. The primary role of fluoride in bone is to strengthen bone mineral.

Water is an important molecular component of bone matrix. Water is initially present in the spaces within the collagen matrix of the unmineralized bone extracellular matrix (osteoid). As crystals fill in the spaces between collagen fibrils, the bone is mineralized and the water is displaced. The water that remains in bone after this process is complete forms hydrogen bonds with polar, hydrophilic components of collagen. Water also assists with the compressive resistance of bone due to osmotic interactions caused by negatively charged proteoglycans.

In addition to calcium, phosphorous, water, and fluoride, the inorganic parts of bone also contain sodium, potassium, carbonate, and magnesium. Although these molecules do not form their own crystals, they are bound to hydroxyapatite crystals within bone mineral.

You can think of the hydroxyapatite in bones as being similar to concrete. The chemical structure of hydroxyapatite gives it a high mechanical strength under compression (squeezing force), but little strength under tension (pulling force). If our bones were made only of hydroxyapatite, they would be very fragile, like concrete. They would break easily under tension. The organic components of bone help to give it additional strength and flexibility.

Collagen, a ropelike, fibrous protein, is the major organic component of bone. Like rope, collagen has significant mechanical strength under tension. Therefore, collagen provides tensile strength to the bones. The spiral arrangement of collagen in combination with its ECM (extracellular matrix) components, such as water and specialized proteins, also makes bone more elastic and less brittle, so that it can absorb shock more easily.

Bone matrix is a network of collagen fibers and hydroxyapatite. It is strong under both tension and compression. Furthermore, the collagen contributes to its ability to absorb sudden forces without breaking.

Collagens are a class of fibrous proteins found in bone, cartilage, and other connective tissues. The primary structure of collagen has repeats of glycine-proline-X, where X can be any other amino acid. This repeated arrangement gives collagen a unique helical secondary structure. The tertiary structure of collagen is a triple helix fibril, which further twists into a quaternary structure of a collagen fiber. The resulting "twisted, twisted, twist" is similar to the higher-ordered structures in rope.

Type I collagen is the primary form of collagen found in bone. The collagen fibers in bone are approximately 300 nanometers long, and are arranged in a staggered pattern. During bone formation, the collagen fiber matrix is deposited first. Proteoglycans are a second class of organic components found in bone. Proteoglycans are macromolecules composed of proteins with negatively charged glycosylated modifications. There are a number of proteoglycans, which are classified by the type of side chains on the core protein. The side chains on the proteoglycans are linear carbohydrates. As with cartilage, the presence of the negatively charged proteoglycans contributes to the resilience of the tissue and retention of water within the matrix. Proteoglycans also bind and release molecules for cell signaling.

Mineralization of the bone matrix occurs when calcium, phosphate, and water from the extracellular fluids combine to form insoluble hydroxyapatite. The hydroxyapatite incorporates into the small pores within collagen fibrils and crystallizes into long, thin, nanosized plates within the collagen network. The incorporation of hydroxyapatite within the collagen fibers contributes to the overall compressive strength of bone. Within the bone matrix, the minerals, water, collagens, and proteoglycans function together to provide strength in tension and compression. Additionally, this unique environment binds and releases chemicals into the extracellular fluids for use throughout the body.

You have already learned about the hydroxyapatite and collagen combination, which is responsible for giving bones their rigidity. The skeletal system is an excellent example of a system that is primarily composed of extracellular matrix. Generally, cells of the body function within a matrix to hold them together. In the case of bone, the extracellular matrix (ECM) is composed of crystals of hydroxyapatite and long collagen proteins. The hydroxyapatite and collagen work together to give bone its unique properties of strength, compressive resistance, and flexibility.

You have learned that bone tissue is classified into two types based on structure: compact bone and spongy bone. The parallel arrays of lamellae are organized into different arrangements depending on the bone structure. The lamellae in compact bone form tubular structures, called osteons. The osteons of compact bone are oriented in the direction of the load-bearing axis. The osteons also create a central canal for the passage of blood vessels. Osteocytes in the osteons are embedded in small cavities called lacunae (singular is lacuna ), and are oriented around the central canal parallel with the lamellae on the load-bearing axis. The diaphyses of long bones are stronger on their long axis than in any other direction, because of the parallel array of osteons and osteocytes.

The lamellae in spongy bone form a random mesh-like structure of interconnecting plates called trabeculae . Likewise, osteocytes within spongy bone are randomly arranged. The strongest trabeculae in spongy bone are arranged on the bone axis that undergoes the most stress. Flat bones of the skull are primarily made of spongy bone and are good at resisting forces from many directions because of the trabecular arrangement.

In both types of bone tissue, the mineral components, calcium and phosphate, combine with collagen to provide the compressive and tensile strength of bone. Spongy and compact bone tissues are combined to create bones, which store and release calcium and phosphate into the blood through constant resorption and deposition. Many bones then articulate with each other to form the skeletal system.

learn by doing

Bones form in two ways. A process known as intramembranous ossification forms bones that develop from layers of connective tissue. Flat bones such as those found in the skull develop through this process. Endochondral ossification (from the word roots endo-, meaning "within," and chondral, meaning "cartilage") is bone formation from a hyaline cartilage blueprint or template, which determines the future bone shape. Bones of the limbs and extremities develop through endochondral ossification. For example, an infant's arm and leg bones contain only small amounts of actual hard bone material; they are primarily made of cartilage. As the child grows, bone replaces the cartilage.

Ossification is the process of forming bone. You learned that there are two types of ossification:

• intramembranous ossification, which is direct synthesis of bone by specialized stem cells (mesenchymal cells) from fibrous connective tissue; and
• endochondral ossification, which is synthesis of bone from a (hyaline) cartilage template.

After bone formation, bone resorption and bone deposition occur continually in a process called bone remodeling to allow for skeletal response to mechanical use, nutritional status and as part of the bone repair and healing process. In the absence of malnutrition or disease, this process maintains homeostasis of both total bone mass and inorganic substances such as calcium and phosphate.

As bones age, they tend to decrease in density and, as a consequence, decrease in strength. In some people, especially women, the bones become very brittle and easily broken. The result is a disorder called osteoporosis . Within bones affected by osteoporosis, bone mass and mineral content decrease. As a result, the bones develop canals filled with fibrous and fatty tissues. This leads to an increased risk of bone fracture because the bone organization that is important to weight bearing is lost.

The microscale structure of a bone gives it significant strength and rigidity, but extreme forces can cause bones to break, or fracture. The table below describes the most common types of fractures.

A bone fracture affects the bone on several levels of organization. A fracture involves a physical break in the mineral structure of the bone. Fractures typically cause blood vessels in the bone to rupture, reducing the blood flow to the bone tissue. As a result, some of the cells in the surrounding bone die. These dead cells and the related cellular debris are removed by immune cells and osteoclasts. Over time, various cell types—fibroblasts, chondroblasts, and osteoblasts—work together to repair the mineralized bone tissue.

Fractures weaken bone, making it less able to perform its functions of support and protection, although once healed, the site of the fracture is stronger than the remaining bone. A fracture may cause a change in the shape of the bone. If that happens, then the way the bone responds to a contracted muscle may change. As a result, fractures can prevent bones from moving correctly when muscles pull on them.

There are pain receptors and nerves in the bone. The pain experienced when a fractured bone moves is one way the body reacts to help itself heal. Bones heal more quickly and thoroughly if they are kept immobilized (which is why the typical treatment for a broken bone is to put it in a cast or other restraint). Because we instinctively avoid actions that cause pain, the pain that occurs when a broken bone is moved causes us to minimize the movement of that bone. This, in turn, helps keep the bone stable while it heals.

Severe fractures, such as compound fractures or comminuted fractures, can cause long-term or permanent disruptions to the body's homeostasis. Because a compound fracture breaks through the skin, bacteria and other pathogens can enter the body after a compound fracture. Those pathogens can enter the bone, blood, muscles, or other tissues or organs, causing severe infection. Severe fractures are also less likely to heal correctly without medical (typically surgical) intervention. Improperly healed fractures can cause changes in the bone's reaction to force, leading to changes in body motion (such as a limp).

The skeletal system provides an excellent example of homeostasis. From the time that we are born, our skeleton must be sufficiently robust to provide stature, protect our soft internal organs and provide a mechanical resistance for our muscles to pull on. However, in addition to the constant need for the skeleton to maintain its function, it must also constantly remodel, otherwise we could not grow. Even in adulthood we constantly develop microfractures that need to be repaired.

The body uses the bones not only for structure and protection, but also for calcium storage. Approximately 99 percent of the body's calcium is stored in the bone, and calcium plays an important role in most of the body's functions. Free calcium levels must remain at a set point for proper body functions. The extracellular levels of calcium are affected by calcium intake from foods, excretion of calcium as waste, and the storage and release of calcium from the bones. Hormones regulate these processes to maintain balanced calcium levels in the extracellular fluid, which is necessary to maintain homeostasis.

Small changes in blood calcium levels can have significant effects on body function. For example, if extracellular calcium levels are too low, the nervous system becomes overexcited, resulting in tetany (rigid, locked muscles). On the other hand, if calcium levels in the body are above normal, the nervous system becomes sluggish. Muscle activity of the heart and gastrointestinal tract slows down.

Milk and dark green vegetables are rich in calcium, and an adequate supply of calcium helps maintain healthy bones. When we eat calcium-rich foods, some calcium is absorbed into the small intestinal wall, and some of the calcium becomes soluble in the blood stream. However, calcium and other divalent cations (ions that are missing two electrons) are poorly absorbed by the small intestine. For this reason, vitamin D is an important dietary supplement. Vitamin D increases calcium absorption in the small intestine.

By altering the function of the osteoblasts and osteoclasts, hormones help regulate calcium levels in the blood. There are three hormones that control osteoblast and osteoclast activity:

• parathyroid hormone or PTH, which increases bone resorption by stimulating osteoblasts, leading to increased calcium release from bone.
• calcitonin, which acts in children to decrease bone resorption, leading to less calcium entering the blood.
• calcitriol, which increases absorption of dietary calcium.
• calcitonin, which acts to decrease bone resorption and increase bone deposition by stimulating osteoblasts.

Parathyroid hormone (produced in the parathyroid glands) controls extracellular calcium by regulating how calcium is reabsorbed in the intestines, excreted from the body, and exchanged between the extracellular fluid and the bone. The cells of the parathyroid gland synthesize and release parathyroid hormone in response to low blood calcium levels. To bring blood calcium levels into the normal range, the release of parathyroid hormone stimulates osteoclasts to reabsorb bone mineral, therefore releasing calcium into the blood. Parathyroid hormone also enhances calcium absorption by the intestines, and prevents calcium loss in urine to increase calcium levels in the blood. When parathyroid cells sense that blood calcium levels are above normal, cellular receptors are activated and the synthesis and release of parathyroid hormone is inhibited.

Calcitonin is produced in the thyroid gland. The function of this hormone is to decrease bone resorption and retain calcium in the bones. Therefore, the effects of calcitonin counteract the effects of parathyroid hormone. When blood calcium levels are high, the thyroid releases calcitonin into the blood. Calcitonin decreases bone resorption by decreasing the activity of osteoclasts and decreasing the formation of new osteoclasts. In this way, calcitonin shifts the bone balance in favor of bone deposition, which requires the removal of calcium from the blood and into the bone. Calcitonin also has minor effects on how the intestines and kidney tubules handle calcium. In adult humans, calcitonin has weak effects on the regulation of calcium levels. We know this because if the thyroid gland is removed, calcium levels are not adversely affected.

Vitamin D is a group of lipid soluble compounds involved in calcium regulation. Vitamin D can be made in the skin through exposure to sunlight, or acquired from the diet and dietary supplements. Under the influence of the parathyroid hormone, vitamin D is converted to an active molecule, calcitriol. Calcitriol circulates through the blood to maintain normal blood calcium levels. When your body does not have sufficient levels of calcitriol, the intestines do not absorb as much calcium, and blood calcium levels decrease. Vitamin D also inhibits calcium loss in urine.

The activity of osteoblasts and osteoclasts in the bone is tightly regulated by the activity of the parathyroid hormone, calcitonin and vitamin D. Nutritional deficiencies in vitamin D, calcium or phosphate lead to a disease called osteomalacia.

Osteomalacia (from osteo-, meaning "bone," and mal-, meaning "bad"), also known as rickets when it occurs in children, is a disease that is most commonly caused by a lack of vitamin D in the body. Remember that vitamin D helps to increase the amount of calcium that the body absorbs and, as a result, helps the body build the mineralized extracellular matrix in bone tissue. If a person lacks sufficient vitamin D, calcium absorption is slowed, and bone growth is affected.

In children, the lack of calcium absorption prevents new bone tissue from ossifying properly. As a result, the bones become weak and rubbery. Because their bones are less able to support the body and withstand the pressure of the body's weight, children with rickets may develop bowed legs and deformed skeletons.

In adults, osteomalacia prevents bones from healing and remodeling properly. Recall that bone tissue is being continually formed and broken down by osteoblasts and osteoclasts. If insufficient calcium is available, the new bone that forms may not calcify properly. As a result, the bones may become painful and brittle.

Osteoporosis is a condition in which the balance between calcium deposition and calcium loss in bones is disrupted. In people with osteoporosis, the bones lose more calcium than they deposit. As a result, the bones become brittle and break easily.

Osteoporosis is most common in post-menopausal women. As a woman goes through menopause, her levels of estrogen decrease significantly. Estrogen and testosterone are important hormones that affect the reproductive system, but they also can stimulate osteoblast activity. As concentrations of these hormones decrease, osteoblasts become less active, and less calcium is deposited in the extracellular matrix. In addition to resulting in weak bones, this is also an issue because there is a reduced reserve of calcium in the body for other tissues.

Osteoporosis can be affected by diet and lifestyle. People who consume very little calcium and vitamin D are at increased risk of osteoporosis. (For example, women with anorexia nervosa, who eat very little, may develop osteoporosis in their late twenties and thirties.) Weight-bearing exercise, such as running, helps to build bone mass and can reduce the chances of developing osteoporosis.

You learned that osteocytes become embedded within bone matrix during mineralization. Within bone lamellae, osteocytes interact with each other through a network of cellular extensions. These extensions, found in a network of canals referred to as canaliculi, allow external mechanical information to be rapidly transmitted to many osteocytes. The response of osteocytes to mechanical force allows our skeletal system to maintain itself.

When bone experiences a mechanical force, this force is transmitted to the fluids and cells within the bone. The forces on the fluids are then transferred through the spaces of the canaliculi down to the osteocytes. In response to the received forces, osteocytes generate a force on the bone tissue. Therefore, the cells and bone matrix constantly respond to each other’s mechanical force input.

Osteocytes in bone tissue act as mechanical strain sensors to convert information about mechanical force into chemical messages. These chemical messages control osteoblast and osteoclast activity and can result in either bone deposition or bone resorption, also known as osteolysis. In response to mechanical force, a two-step process occurs. First, mechanically sensitive membrane proteins on the surface of the osteocytes are activated. Second, chemical pathways within the osteocytes are activated. Activation of these intracellular pathways stimulates osteoblast activity and inhibits osteoclast activity.

As you learned earlier, bone ECM (extracellular matrix) maintains the mechanical structure and functional properties of bone tissue. The collagen fibers of bone ECM are under constant tension so that the bone ECM is always ready to respond to mechanical force. Because osteocytes are attached to the ECM, the tension felt by the collagen fibers is balanced by the tension that osteocytes place on the ECM. Therefore, osteocytes sense mechanical force and transmit this force to the surrounding ECM. Bone ECM is constantly remodeled to maintain optimal strength for applied mechanical force.

Mechanical forces control osteoblast and osteoclast activity through feedback from the osteocytes and the ECM. One common type of mechanical force is physical activity. Another force that is not as obvious is body mass. With increased mechanical force, such as physical activity or weight gain, bone ECM increases to support the force. When the mechanical force applied to bone is too high, osteocytes within bone matrix signal for remodeling through bone resorption and bone deposition.

People who routinely lift heavy loads have very strong bones, but the body spends a lot of energy to maintain these stronger bones. On the other hand, sedentary individuals may lose bone density and strength. However, that can be a problem: a lack of exercise, extended bed rest and space travel (for astronauts), during which there is little or no force on bones because of inactivity or weightlessness, can cause a significant loss of bone mass.

You have learned in relation to ossification how cartilage and bone are inherently integrated. Both tissue types are also some of the most force-responsive in the body. This is necessary to maintain stature. Chondrocytes sense force and changes in water movement—associated with the force-induced movement of water—and secrete the appropriate collagen and proteoglycan extracellular matrix proteins.

Recall that cartilage is composed primarily of a network of elastic type II collagen fibers embedded in gel-like proteoglycans. Water, electrolytes, and chondrocytes are interspersed within the network. The physical properties of collagen and proteoglycans are largely responsible for the ability of cartilage to respond flexibly to force.

Collagen fibers have significant tensile strength, which means that they can withstand a lot of tension (pulling) without damage. However, collagen fibers have very little compressive strength—that is, under compression (squeezing), they bend easily. You can think of a collagen fiber as a rubber band or string. If you pull on a rubber band, it stretches easily, and then returns to its original shape when you stop pulling. However, if you push on the ends of the rubber band, it folds up easily—it has minimal strength.

Collagen fibers are what give cartilage its strength. The cartilage in different areas of the body contains fibers that are arranged in different ways. The orientation and arrangement of the collagen fibers helps to give each region of cartilage strength to withstand specific types of stress. For example, articular cartilage—the cartilage that forms the articulating surfaces of joints, such as the knee—contains two main regions of collagen fiber orientation. At the surface of the cartilage, the fibers are arranged primarily parallel to the surface. Further from the surface, the fibers are arranged primarily perpendicular to the surface.

Proteoglycans are gel-like, elastic substances. They are highly resilient, which means that they deform easily under stress, but return to their original shape when the stress is removed. Proteoglycans give cartilage its resiliency and elasticity.

The combination of strength and elasticity allows cartilage to respond flexibly and quickly to forces placed on it. For example, the cartilage in your knee can support up to eight to 10 times your body weight for short periods without being damaged. As more force acts on the cartilage, it compresses. Its elasticity allows it to distribute the force evenly, and its strength allows it to withstand the stress without breaking or collapsing. When the stress is removed, the cartilage returns to its original shape. The physical movement of the water in the cartilage also helps to distribute the force of compression.

Cartilage is less complex in response to force than bone, which has multiple integrated cell types. Cartilage is less regulated by hormones, is difficult to overgrow, and grows extremely slowly. Part of the reason for slow growth is a limited amount of nutrients. Cartilage is avascular (a- means "none"), so there are no blood vessels or blood supply to the interior of the cartilage, so nutrient travel is limited to diffusion, and growth is limited.

Arthritis (from arthro-, meaning "joint," and –itis, meaning "inflammation") is any inflammation of the cartilage and/or bone tissue within a joint. The most common form of arthritis is osteoarthritis, which is caused primarily by physical damage to the cartilage that cushions many joints. The damage may be caused by a decrease in cartilage flexibility and water content as a person ages, but it may also be a secondary result of a variety of other conditions (including diabetes and mechanical injury to the joint). Osteoarthritis is most common in the elderly, but can affect younger people as well.

Osteoarthritis begins with physical damage to cartilage tissue in the joints. The damage may be cellular (such as damage cause by an infection), or it may occur at the tissue level. The damage causes the cartilage to break down. As the cartilage breaks down, friction within the joint increases; in severe cases, the ends of the bones themselves may rub together, causing severe pain. Loss of cartilage can also reduce the flexibility of the joint. Pain and loss of flexibility typically cause a person to move the joint less; as a result, the muscles, tendons, and ligaments near the joint may weaken. This in turn can cause additional difficulty moving the joint.

A different form of arthritis that also causes joint pain, rheumatoid arthritis, is caused by inflammation of the membranes of the synovial capsule, not the articular cartilage.

The homeostatic control of blood (plasma) calcium levels requires interactions between several body systems. Roughly 1000 mg of calcium per day is taken into the body by ingestion, 350 mg of calcium per day is absorbed into the digestive system and the rest is excreted. Of the calcium absorbed by the digestive system and from there into the cardiovascular system, some is processed through the urinary system. Calcium exchange between cells, extracellular fluid and the bones is partly regulated by the endocrine system, which directs bone degradation if more calcium is needed in other parts of the body. The endocrine system also stimulates osteoclasts, which are cells derived from the precursor cells of the immune system. The calcium liberated by the bones is used by the nervous system and the muscular system to keep many of their functions working appropriately.

Systems within the body are integrated with respect to dysfunction as well. Osteoarthritis is the most common form of arthritis, and as you have learned, it is caused by mechanical damage to the cartilage. Rheumatoid arthritis, in contrast, is an autoimmune disease—that is, a disease in which the body's immune system attacks normal tissue. In rheumatoid arthritis, the immune system attacks healthy cartilage and synovial membranes.

Immune cells attack the synovial membranes in synovial joints, causing inflammation. As the membrane becomes inflamed and thickened, synovial fluid begins to accumulate in the joints. The joints can become swollen and painful, and it becomes more difficult for the bones in the joint to slide past one another. Over time, fibrous tissue forms in the joint. Eventually, the fibrous tissue fuses the two bones together, preventing the joint from moving.

When you think of muscles you probably have a picture in your mind of some muscular people who are pleasing to the eye. Did you know that you have over 650 muscles in your body? That sounds like a lot but a caterpillar has even more, around 4000 muscles! Without muscles we would never be able to move. The main function of the muscular system is movement. But did you know that muscle contractions generate 85% of our body heat? Muscles also protect our organs. Your abdominal muscles keep your “guts” and internal organs in place. Some muscles are circular, such as the one that encircles your mouth for kissing or puckering. Other circular muscles form sphincters which control when you defecate or urinate. One important muscle, known as your diaphragm, is necessary for breathing. If your diaphragm stopped working you would die in minutes because you would not breathe.

Let’s test your knowledge on some common facts and myths of the muscular system.

Let’s check out the muscular system in action in the following case study.

Seymour is a nineteen year old power lifter and college student. You sit next to Seymour in psychology class and have gotten to know him this semester. On Monday, he sits down next to you and lets out a wince of pain as he takes his seat. You ask him, “What’s wrong?”

He replies, “Oh, it’s probably nothing, but my stomach has been hurting especially when I lift something heavy.”

“Don’t you work at The Dark Horse Tavern? And work out a lot? I bet that must be tough on you. Do you think you pulled a muscle?” you ask him.

Seymour answers, “I don’t know, I’ve never felt this kind of pain before, it hurt a lot at work and I haven’t been able to lift as much at the gym.”

“Why don’t we check this out on my iPhone, we still have 5 minutes before class begins” you reply.

Seymour suggests going to WebMD.com for a quick look. “Hmm, I don’t see anything specific for stomach pain while exercising,” you tell him. “What other symptoms do you have?”

“Well, it’s kind of embarrassing but I have noticed this lump in my navel especially while lifting.”

“My cousin had something like that before, I think it was called a hernia, let’s Google that. Oh – man, it sounds like something called an umbilical hernia, it says that the bulge might be your intestines!” you whisper to him. “Seymour, you better get to your doctor right away, this can’t be good.”

Seymour goes a little pale and says, “I’m going to call my mom right after class.”

The muscular system is mainly composed of skeletal muscle, such as those that cover the anterior portion of your abdomen and help compress the abdominopelvic cavity and digestive organs. As we saw with Seymour, if these muscles are weakened, they might separate and allow the underlying organs to protrude. Seymour’s constant exposure to high intra-abdominal pressure has weakened the muscle. If a piece of Seymour’s intestine is bulging through his abdominal muscles this can have serious consequences. The small intestine is a critical component of the digestive system and if it is pinched off that section could become necrotic and die.

There are two other types of muscle tissue that are necessary for life: cardiac and smooth muscle. Cardiac muscle is found in the heart and its rhythmic contraction is responsible for your heart beat, while smooth muscle is found in many organs and blood vessels. Smooth muscle is a significant part of your cardiovascular system (blood vessels), respiratory system (bronchioles), digestive system (esophagus, stomach, small and large intestines), urinary system (ureters and urinary bladder), and your reproductive system (uterus, vas deferens).

As stated earlier, skeletal muscle has many important functions in maintaining our homeostasis. Skeletal muscle contractions are critical in producing heat for our body. In fact, when you are very cold your skeletal muscles increase contractions to generate more heat to warm you – this is known as shivering. When you exercise and your skeletal muscles are more active you produce more body heat and your body temperature increases. Your body will sweat to help cool itself.

The diaphragm is a skeletal muscle that contracts to allow us to inhale, we exhale when it relaxes. Any disruption in this important muscle’s function can be fatal. The diaphragm is a critical organ of the respiratory system.

Clearly, skeletal muscle and muscle tissue is much more important than just giving us a “buff” body!

The muscular system consists of skeletal muscle connected to bones via tendons. Tendons are a type of dense regular connective tissue that joins muscles to bone. The abdominal muscles are also held with broad tendon sheaths termed aponeuroses. In Seymour’s case either the muscle separated or pulled away from its aponeurosis that helped to anchor the muscle fibers together.

As mentioned, there are three types of muscle tissue. Skeletal muscle attaches to bones, is voluntary, and has a striped (striated) appearance. Cardiac muscle is found in the heart, is involuntary and is striated. Smooth, sometimes known as visceral muscle, is found in many organs and blood vessels, is not striated but is involuntary.

All muscle tissue is composed of muscle cells known as muscle fibers. These fibers are bundled and held together with connective tissue. The basic unit of the muscle cell is the sarcomere. Muscles contract because sarcomeres shorten. Calcium is essential for all types of muscle tissue to function properly. You will investigate the role of calcium in muscle contraction in this module.

Muscle contains many proteins, mainly myosin and actin. Skeletal muscle is under control of the nervous system and will not contract unless a neural command reaches the muscle and instructs it to do so. The nervous system communicates with skeletal muscle via chemical messengers known as neurotransmitters. The neurotransmitter, acetylcholine, is responsible to stimulating skeletal muscle so it contracts. The process of muscle contraction occurs at the cellular level and will be studied in this unit.

Muscle fibers or cells are not all alike. There are cells that are specialized for endurance events, these are known as slow-twitch fibers. There are also cells or fibers that are better suited for power and sprinting. These fatigue a lot faster and are known as fast-twitch fibers.

When you study the muscular system you will need to understand the microscopic anatomy and physiology so you can learn how muscle contracts. You will also study the gross anatomy of muscles, their names, locations, and functions in the human body. The muscular system is a fascinating system. Enjoy your journey as you discover it!

Skeletal muscles, which are the organs of the skeletal muscle system, include three layers of connective tissue that enclose and provide structure to the muscle as a whole. The outer layer of each muscle fiber is wrapped with a layer of connective tissue called the epimysium ("epi-" means "outside" or "over," and "-mysium" refers to "muscle"). The epimysium allows muscle to contract and move powerfully while maintaining its structural integrity; it also separates muscle from other tissues and organs. It is composed of a thick layer of collagen fibers. The epimysium is surrounded by fascia, which is a type of connective tissue that is found around body organs. Deep fascia surrounds groups of muscles, sometimes joining with tendons to strengthen the bone attachment, whereas superficial fascia lies between muscle and skin. Some fascia contain adipose tissue that insulates and protects muscle.

Inside each skeletal muscle, muscle fibers (a single muscle cell is called a muscle fiber; not to be confused with fibers found in connective tissue) are organized into groups called fascicles, or bundles of muscle fibers (cells). Some of these fascicles can be seen without a microscope when a muscle is cut open. Each fascicle contains many long muscle fibers bound by a middle layer of connective tissue called the perimysium ("peri-" means "around"). Similar to the epimysium, the perimysium contains collagen fibers, but the perimysium also contains elastic fibers.

Inside each fascicle, each individual muscle fiber is encased in a connective tissue layer called the endomysium ("endo-" means "inside"). The endomysium forms a thinner layer than the dense epimysium and perimysium, and contains areolar and reticular tissues which form loose, delicate networks. The endomysium of muscle fibers connect to each other to form a loose complex within a fascicle. Small blood vessels and motor neurons pass through the endomysium to support and activate each muscle fiber.

The plasma membrane, or sarcolemma, of a skeletal muscle fiber is located just under the endomysium. The sarcolemma is the site of action potential conduction, which triggers muscle contraction. Within the sarcolemma is the sarcoplasm, the cytoplasm of the muscle cell.

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The fascicles of parallel muscles are arranged parallel to the long axis of the muscle. They are equidistant and run in the same direction. The majority of skeletal muscles in the body follow this type of organization. With muscles that seem to be plump, the large mass of tissue located in the middle of the muscle is known as the central body, but its more common name is the belly. When the muscle contracts, the contractile fibers shorten into a large bulge. To see this, extend and then flex your biceps muscle. The large mass of the muscle is called the belly; tendons emerge from both ends of the muscle. When a muscle contracts, it is the pulling on the tendon by the muscle that actually produces the movement.

The fascicles of circular muscles, also called sphincters, are arranged around an opening in rings. When the muscle contracts, the size of the sphincter opening decreases. The orbicularis oris muscle is a circular muscle around the mouth under the lips. Another example is the orbicularis oculi ("ocular" means "eye"), which surrounds each eye. The circular muscles expand and contract in a circular way. The circular muscles contract and relax in a circular way. Think about how you can contract and shape your lips to whistle or pucker.

In convergent muscle, the fascicles extend from a broad, fan-shape area and converge on single attachment site where the muscle interacts with a tendon. .The large muscle on the chest, the pectoralis major, is an example of a convergent muscle. Because of the arrangement of motor units within a convergent muscle, it can be stimulated in different, smaller areas. This can change the direction of the muscle force slightly from when the entire muscle contracts at once.

Pennate muscles are feather-shaped and form different fascicle arrangements at an angle to the tendon. Contracting pennate muscles pull at an angle and can produce high tension, but don’t move tendons very far. There are three subtypes of pennate muscles: unipennate, bipennate, and multipennate muscles. In unipennate muscles, such as the extensor digitorum in the forearm, the fascicles are located on one side of the tendon. A bipennate muscle, such as the rectus femoris in the thigh, has fascicles on both sides of the tendon. If the tendon branches within a pennate muscle, as it does in the deltoid muscle of the shoulder, the muscle is referred to as multipennate.

Some parallel muscles are fusiform and have fascicles that are spindle-shaped to give the muscle a large belly, such as the biceps brachii, whereas triangular muscles can be convergent or multipennate to create triangular shapes. Triangular muscles include the trapezius, which extends from the head down the back and out to the shoulder.

Skeletal muscles, which are the organs of the skeletal muscle system, generally act by pulling on bones to produce movement. To pull the bone, muscles need to attach to the bone, either directly or indirectly. The epimysium of a muscle can attach directly to bone or cartilage to form a direct attachment. An indirect attachment is formed when the connective tissue layers, the epimysium, perimysium, and endomysium form a complex at the end of the muscle.

For connections, muscles require either a tendon or a broader sheet of connective tissue called an aponeurosis. Muscles connect to muscles via aponeuroses, and muscles attach to bones via tendons or aponeuroses. Thus, when a muscle contracts, the force of movement is transmitted through the attachment, which pulls on the bone to produce skeletal movement.

Tendons also help to stabilize the joints. Tendons are a common form of attachment because the collagen fibers are more resistant to tearing than direct muscle tissue attachment to bone would be, and the compact form of the tendon requires a small amount of space. Tendons can be easily seen as the hand is flexed, causing the thick, cordlike tendons of the forearm to stand out prominently. The calcaneal (Achilles) tendon is visible from the heel to the calf. Some tendons are also surrounded by a connective tissue layer called a tendon sheath, which protects the tendon as it moves. Fluid-filled sacs called bursae also join to tendons to reduce friction as the tendon moves. Bursae are present in connective tissue near bone, where tendons experience friction, but they occasionally arise in other areas due to stress caused by movement.

Keep in mind that the range of motion produced by muscles is restricted by the anatomy of the bones and other support structures involved in a particular joint. Consider the movements of the hip and shoulder joints, both of which are freely moveable. The hip is the attachment point for the thigh and leg. The shoulder is the attachment point for the arm and forearm. The shoulder can produce movements that the hip cannot because of the anatomy of the bones involved and the ligaments (connective tissue) associated with the joint. Hold your arm out to the side and move your thumb around the axis of the arm in a 360-degree circle. Can you do that with your hip and leg? No, you can’t. There are some people who appear to be “double-jointed"; they are able to push their joints past the normal limits of movement. The reason they can do this is because the ligaments of their joints are “loose” compared with someone who is not “double-jointed.” This ability appears to have a genetic basis.

For muscles attached to the bones of the skeleton, the location of the connection determines the force, speed, and type of movement. These characteristics depend on each other and can explain the general organization of the muscular and skeletal systems.

We can consider the mechanisms by which muscles act on bones using descriptions based on levers. A lever is a rigid structure, in this case a bone, that moves on a fixed point called the fulcrum, in this case an articulation. A lever moves when an applied force or effort is sufficient to overcome any load or resistance that would otherwise oppose or prevent such movement. In the body, each bone is a lever and each joint is a fulcrum, and muscles supply the applied forces. Movement of the skeleton occurs at joints, so there has to be sufficient muscle power to move all the bones at these joints.

Levers can change the direction and effective strength of a force as well as the distance and speed of movement produced by the force. Imagine a seesaw in a playground. You and a friend could sit on opposite ends of it. You would then take turns pushing off the ground with your legs as you each went up in the air. A seesaw is an example of a first-class lever, and there are three classes of levers. The fulcrum (F) lies at the midpoint of the seesaw, between the applied force (AF) and the load (L). What this means is that the seesaw balances you and your friend, as you both provide the applied force with the push of your legs and the load with the weight of your bodies.

The body has only a few first-class levers. One is involved in head flexion (pulling the head down toward the chest) and head extension (pulling the head back up into normal position). The fulcrum is where the head moves in the sagittal plane on the first cervical vertebrae. The load is the weight of the head, and the applied force comes from the muscles. Extension occurs when the muscles pull the head back up. Moving your head forward and backward mirrors the action of a seesaw.

In a second-class lever, the load is located between the applied force and the fulcrum. When you move a load in a wheelbarrow, you lift upward on the handle and the wheel acts as the fulcrum. The force is further from the fulcrum than the load is, so you can move a larger weight with less effort. In the body, you achieve the same effect by standing on your toes. The fulcrum is on the ball of the foot, the load is your body weight, and the effort comes from the muscles in the back of the leg.

In third-class levers the force is applied between the load and the fulcrum. We don’t often see these types of levers in artificial machines, but they are the most common levers in the body. Speed and distance traveled are increased at the expense of force. For the biceps brachii in the arm, the load will be located in or around the hand. The biceps muscle applies the force, while the fulcrum is the elbow. For instance, when you pick up a full bag of groceries, you can lift it quickly using the third-class lever of the biceps brachii and the forearm. However, the location of fulcrum prevents great enhancements of load carrying.

Skeletal muscles are arranged in pairs for balance and to work efficiently.

Some muscles function as agonists, or prime movers. An antagonist is a muscle that opposes the action of the agonist. When an agonist contracts to produce a movement, the corresponding antagonist will be stretched and contract with sufficient tension to control the movement. For instance, when your biceps muscle acts to flex your forearm, the triceps muscle contracts slightly to prevent you from flexing your forearm too quickly or too strongly.

Agonist and antagonist muscles work against one another to control and balance movements. Other muscles, called synergists (from synergy, to work together), improve the efficiency of an agonist muscle. Synergists may provide additional pull or stabilization, and their assistance to a particular movement may change throughout the progression of the movement.

This table provides examples of agonist-antagonist combinations.

The force generation required for skeletal muscle function occurs at the molecular level. You can develop a better understanding of the properties of cells and tissues by studying the molecular mechanisms common to the cells involved:

• Molecular level — actin and myosin
• Microscopic level — sarcomere and myofibrils
• Cell level — myoblasts and myofibers
• Tissue level — neuromuscular junctions and fascicles
• Organ level — major skeletal muscles of the body

Myosin is a protein that converts the chemical energy stored in the bonds of ATP into the kinetic energy of movement. Myosin is the force-generating protein in all muscle cells, and a coordinated effort among many myosin molecules pulling on actin, generates force for movement. Myosin molecules have two main structural parts. The tail of a myosin molecule consists of two polypeptide subunits wound together, whereas the head is composed of two globular subunits. The tail of a myosin molecule connects with other myosin molecules to form the central region of a thick filament, whereas the heads align on either end of the thick filament where thin filaments overlap with the thick filament. The point at which the head and tail of the molecule meet is flexible and allows the head to move back and forth. This allows myosin to “walk” and pull on actin filaments. Actin filaments are made of individual globular (spherical) protein subunits that assemble linearly into helical (twisted) filaments.

ATP binding to myosin causes it to release actin, allowing actin and myosin to detach from each other. After this occurs, ATP is converted to ADP and Pi. The binding site on myosin that hydrolyzes ATP to ADP is called ATPase. The energy released during ATP hydrolysis changes the angle of the myosin head into a “cocked” position. The myosin head is then in a position for further movement, possessing potential energy; however, ADP and Pi are still attached.

Cross-bridge formation occurs at this point, as actin binds while ADP and Pi are still bound to myosin. Pi is then released, causing myosin to form a stronger attachment to actin, and the myosin head moves toward the M line, pulling actin along with it. As actin is pulled, the filaments move approximately 10 nanometers toward the M line. This movement is called the power stroke, as the thin filament “slides” over the myosin and ADP is released during this step.

When the myosin head is “cocked,” myosin is in a high-energy configuration. This energy is expended as the myosin head moves through the power stroke. At the end of the power stroke, the myosin head is in a low-energy position. Each myosin molecule may form many cross-bridges during muscle contraction. The collection of power strokes and cross-bridges allows collections of individual molecules to generate large forces.

In skeletal muscle, tropomyosin and troponin regulate contraction by controlling the interaction between actin and myosin filaments. Tropomyosin acts to block myosin binding sites on the actin filament, preventing cross-bridge formation and thus preventing contraction in a relaxed muscle. Calcium triggers muscle contraction by binding to troponin and altering its shape so that tropomyosin does not block the myosin binding sites on actin, thus allowing muscle contraction to occur. Calcium is generally an important molecule in muscle function, as we will discuss later.

Titin, as the name implies, is a very large structural protein in muscle cells. Unlike actin and myosin, which bundle together to form a multiprotein complex, titin is a single protein that holds large structures together. Thus, titin is a large, multifunctional protein (hundreds of times bigger than these other proteins) that forms an elastic filament. Titin helps align the myosin proteins and allows the muscle cell to maintain structural integrity by resisting extreme stretching, preventing damage due to overstretching.

Dystrophin is a protein that helps bind actin to the muscle cell membrane. Insufficient dystrophin production results in an inability to transfer the force of the organized actin-myosin contraction to the muscle cell membrane and ultimately to the tendons. Loss or insufficient production of this molecule causes Duchenne muscular dystrophy (DMD).

The fundamental functional unit of muscle is called a sarcomere. One muscle may contain as many as 100,000 of the repeating sarcomere units. In the sarcomere, the myofilaments (thick filaments and thin filaments) are organized into parallel units. Sarcomeres were first identified by imaging (histology), and the nomenclature described below reflects their microscopic "appearance."

Molecular Organization of Muscle

Myofilaments are organized structures in muscle cells that contain the actin and myosin. The organized globular proteins of actin in muscle cells form a thin filament, and bundles of over 200 myosin proteins form a thick filament. The thick filament myosin heads “walk” along the actin thin filaments. A single thin filament is composed of 300-400 globular actins with 40-60 troponin and tropomyosin molecules. A single thick filament is composed of more than 200 myosin molecules.

Actin filaments are thin, causing the actin "rope" to appear skinny. The myosin filament contains many myosins bundled up with all of the head groups sticking out, so that it looks “fluffy.” That fluffiness makes it look thick.

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Sarcomere Anatomy—H Zone, M Line, Z Disc, I Band and A Band

Histological sections of muscle show the anatomical features of the sarcomeres. Thick filaments, composed of myosin, are visible as the A band of a sarcomere. Thin filaments, composed of actin, attach to a protein in the Z disc (or Z line) called alpha-actinin, and they are present across the entire length of the I band and a portion of the A band. The region where thick and thin filaments overlap has a dense appearance, as there is little space between the filaments. This zone where thin and thick filaments overlap is very important to muscle contraction, as it is the site where filament movement starts. Thin filaments do not extend completely into the A bands, leaving a central region of the A band that only contains thick filaments. This central region of the A band looks slightly lighter than the rest of the A band, and is called the H zone. The middle of the H zone has a vertical line called the M line, where accessory proteins hold together thick filaments.

Microscopically Visible Feature	Composition
A band	Region of thick-filament myosin proteins
H zone	Central region of the A band with no overlapping actin proteins when muscle is relaxed
I band	Region of thin-filament actin proteins, with no myosin
M line	M line accessory proteins in center of myosin thick filament perpendicular to the sarcomere
Z disc	Zig-zag line of Z line proteins and actin binding proteins perpendicular to the sarcomere

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Smooth muscle tissue is found in many different body systems, including as part of organs in the digestive, respiratory, and reproductive tracts and in the walls of blood vessels. Smooth muscle cells are approximately the same size as cardiac muscle cells and also have only one nucleus. However, smooth muscle cells are not branched and, unlike both cardiac and skeletal muscle, smooth muscle cells don't have sarcomeres. Smooth muscle cells form layers that are usually arranged so that one runs parallel to an organ and the other wraps around it. These two muscle layers then contract in turn, causing alternating dilation and contraction or lengthening and shortening of the organ, moving substances through internal passages. This is called peristalsis and is displayed in the process of digestion as food moves through the gastrointestinal tract.

Similar to skeletal and cardiac muscle cells, smooth muscle can undergo hypertrophy to increase in size. Unlike the other two muscle types, mature smooth muscle cells can also divide to produce more cells, a process called hyperplasia. This can be observed in the uterus, which responds to increased estrogen levels by producing more uterine muscle cells.

Smooth muscle cells also do not possess T tubules and do not have a very extensive sarcoplasmic reticulum. Smooth muscle has actin and myosin but they are not organized into sarcomeres, so there are no obvious bands or striations. Instead, actin and myosin is organized into dense bodies attached to the sarcolemma, shortening the muscle cell as thin filaments slide past thick filaments. Thin and thick filaments are aligned in a diagonal pattern across the cell so that contraction produces a twisting or corkscrew motion, rotating one way as it contracts and the other way as it relaxes. Cross-bridge formation and filament sliding processes are the same in smooth muscle as they are in skeletal and cardiac muscle. Actin, myosin, and tropomyosin are all present, but smooth muscle cells do not possess troponin as their regulatory protein. Instead, a molecule called calmodulin binds to calcium and activates myosin cross-bridge formation. There is also a greater ratio of actin to myosin in smooth muscle, meaning that there are more thin filaments for every thick filament.

Most smooth muscles must function for long periods without rest, so their power output is relatively low, but contractions can continue without utilizing large amounts of energy. This occurs because the ATPase in myosin works at a relatively slow rate, meaning that high levels of ATP are not available for powerful contractions but a steady supply is produced for sustained contractions. Smooth muscle can also maintain contractions through a latch state, during which actin and myosin remain locked together, or latched, in the absence of Ca2+ ions. This does not require ATP, thereby producing sustained contractions without using energy. This allows smooth muscles to keep your blood vessels partially contracted for your entire life without them fatiguing.

Similar to cardiac muscle, smooth muscle is not under voluntary control. In addition to spontaneous stimulation, smooth muscle can be stimulated by pacesetter cells that are similar to pacemaker cells and trigger waves of action potentials in smooth muscle. Smooth muscle can also be stimulated by the autonomic nervous system or hormones. Neuromuscular junctions are not present in smooth muscle, but varicosities, enlargements along autonomic nerves, release neurotransmitters into synaptic clefts. Smooth muscle can respond to a variety of neurotransmitters to produce different effects at different locations.

Smooth muscle can be divided into two types based on how depolarization and muscle contraction occur. Single-unit smooth muscle cells contain gap junctions, which allow the cells to be electrically coupled. Electric couplings allow action potentials to spread quickly from one cell to the next, permitting coordinated depolarization and contraction. In this manner, groups of muscle cells act as a single unit, contracting in unison. This type of smooth muscle is found in hollow organs, including the gastrointestinal tract, and in the walls of small blood vessels, and it is often stimulated spontaneously or by stretching, to produce an action potential.

Multiunit smooth muscle cells rarely possess gap junctions, so they are not electrically coupled. Stimuli for multiunit smooth muscles come from autonomic nerves or hormones but not from stretching. This type of tissue is found in the walls of large blood vessels, in the respiratory airways, and connected to hair follicles (to make your hair "stand up”), among other places.

Skeletal muscle cell contraction occurs after a release of calcium ions from internal stores, which is initiated by a neural signal. Each skeletal muscle fiber is controlled by a motor neuron, which conducts signals from the brain or spinal cord to the muscle.

The following list presents an overview of the sequence of events involved in the contraction cycle of skeletal muscle:

1. The action potential travels down the neuron to the presynaptic axon terminal.
2. Voltage-dependent calcium channels open and Ca²⁺ ions flow from the extracellular fluid into the presynaptic neuron's cytosol.
3. The influx of Ca²⁺ causes neurotransmitter (acetylcholine)-containing vesicles to dock and fuse to the presynaptic neuron's cell membrane.
4. Vesicle membrane fusion with the nerve cell membrane results in the emptying of the neurotransmitter into the synaptic cleft; this process is called exocytosis.
5. Acetylcholine diffuses into the synaptic cleft and binds to the nicotinic acetylcholine receptors in the motor end-plate.
6. The nicotinic acetylcholine receptors are ligand-gated cation channels, and open when bound to acetylcholine.
7. The receptors open, allowing sodium ions to flow into the muscle's cytosol.
8. The electrochemical gradient across the muscle plasma membrane causes a local depolarization of the motor end-plate.
9. The receptors open, allowing sodium ions to flow into and potassium ions to flow out of the muscle's cytosol.
10. The electrochemical gradient across the muscle plasma membrane (more sodium moves in than potassium out) causes a local depolarization of the motor end-plate.
11. This depolarization initiates an action potential on the muscle fiber cell membrane (sarcolemma) that travels across the surface of the muscle fiber.
12. The action potentials travel from the surface of the muscle cell along the membrane of T tubules that penetrate into the cytosol of the cell.
13. Action potentials along the T tubules cause voltage-dependent calcium release channels in the sarcoplasmic reticulum to open, and release Ca²⁺ ions from their storage place in the cisternae.
14. Ca²⁺ ions diffuse through the cytoplasm where they bind to troponin, ultimately allowing myosin to interact with actin in the sarcomere; this sequence of events is called excitation-contraction coupling.
15. As long as ATP and some other nutrients are available, the mechanical events of contraction occur.
16. Meanwhile, back at the neuromuscular junction, acetylcholine has moved off of the acetylcholine receptor and is degraded by the enzyme acetylcholinesterase (into choline and acetate groups), causing termination of the signal.
17. The choline is recycled back into the presynaptic terminal, where it is used to synthesize new acetylcholine molecules.

Acetylcholine, often abbreviated as ACh, is a neurotransmitter released by motor neurons that binds to receptors in the motor end-plate. It is an extremely important small molecule in human physiology. On the neuron side of the synaptic cleft, there are typically 300,000 vesicles waiting to be exocytosed at any time and each vesicle contains up to 10,000 molecules of acetylcholine.

ACh is produced by the reaction of Acetyl coenzyme A (CoA) with a choline molecule in the neuron cell body. After it is packaged, transported, and released, it binds to the acetylcholine receptor on the motor end-plate; it is degraded in the synaptic cleft by the enzyme acetylcholinesterase (AChE) into acetate (and acetic acid) and choline. The choline is recycled back into the neuron. AChE resides in the synaptic cleft, breaking down ACh so that it does not remain bound to ACh receptors, which would interrupt normal control of muscle contraction. In some cases, insufficient amounts of ACh prevent normal muscle contraction and cause muscle weakness.

ATP supplies the energy for muscle contraction to take place. In addition to its direct role in the cross-bridge cycle, ATP also provides the energy for the active-transport Na⁺/K⁺ and Ca²⁺ pumps. Muscle contraction does not occur without sufficient amounts of ATP. The amount of ATP stored in muscle is very low, only sufficient to power a few seconds worth of contractions. As it is broken down, ATP must therefore be regenerated and replaced quickly to allow for sustained contraction.

One ATP moves one myosin head one step. This can generate three picoNewtons (pN) of isometric force, or move 11 nanometers. Three pN is a very small force—a human bite, generated by muscle, can generate 500 trillion pN of force. And 11 nm is a very small distance— one inch has 25 million nanometers.

There are three mechanisms by which ATP can be regenerated: creatine phosphate metabolism, anaerobic glycolysis, and aerobic respiration.

Creatine phosphate is a phosphagen, which is a compound that can store energy in its phosphate bonds. In a resting muscle, excess ATP (adenosine triphosphate) transfers its energy to creatine, producing ADP (adenosine diphosphate) and creatine phosphate. When the muscle starts to contract and needs energy, creatine phosphate and ADP are converted into ATP and creatine by the enzyme creatine kinase. This reaction occurs very quickly; thus, phosphagen-derived ATP powers the first few seconds of muscle contraction. However, creatine phosphate can only provide approximately 15 seconds worth of energy, at which point another energy source has to be available.

After the available ATP from creatine phosphate is depleted, muscles generate ATP using glycolysis. Glycolysis is an anaerobic process that breaks down glucose (sugar) to produce ATP; however, glycolysis cannot generate ATP as quickly as creatine phosphate. The sugar used in glycolysis can be provided by blood glucose or by metabolizing glycogen that is stored in the muscle. Each glucose molecule produces two ATP and two molecules of pyruvate, which can be used in aerobic respiration or converted to lactic acid.

If oxygen is available, pyruvic acid is used in aerobic respiration. However, if oxygen is not available, pyruvic acid is converted into lactic acid, which may contribute to muscle fatigue and pain. This occurs during strenuous exercise when high amounts of energy are needed but oxygen cannot be delivered to muscle at a rate fast enough to meet the whole need. Anaerobic glycolysis cannot be sustained for very long (approximately one minute of muscle activity), but it is useful in facilitating short bursts of high-intensity output. Glycolysis does not utilize glucose very efficiently, producing only two ATP molecules per molecule of glucose, and the by-product lactic acid contributes to muscle fatigue as it accumulates. Lactic acid is transported out of the muscle into the bloodstream, but if this does not happen quickly enough, lactic acid can cause cellular pH levels to drop, affecting enzyme activity and interfering with muscle contraction.

Aerobic respiration is the breakdown of glucose in the presence of oxygen to produce carbon dioxide, water, and ATP. Aerobic respiration in the mitochondria of muscles uses glycogen from muscle stores, blood glucose, pyruvic acid, and fatty acids. Approximately 95 percent of the ATP required for resting or moderately active muscles is provided by aerobic respiration. Aerobic respiration is much more efficient than anaerobic glycolysis, producing approximately 38 ATP molecules per molecule of glucose. However, aerobic respiration does not synthesize ATP as quickly as anaerobic glycolysis, meaning that the power output of muscles declines, but lower-power contractions can be sustained for longer periods.

This combination of different energy sources is important for different types of muscle activity. As an analogy, a cup of coffee with lots of sugar provides a quick burst of energy but not for very long. A balanced meal with complex carbohydrates, protein and fats takes longer to impact us, but provides sustained energy.

Muscles require a large amount of energy, and thus require a constant supply of oxygen and nutrients. Blood vessels enter muscle at its surface, after which they are distributed through the entire muscle. Blood vessels and capillaries are found in the connective tissue that surrounds muscle fascicles and fibers, allowing oxygen and nutrients to be supplied to muscle cells and metabolic waste to be removed. Myoglobin, which binds oxygen similarly to hemoglobin and gives muscle its red color, is found in the sarcoplasm.

You have already learned about the anatomy of the sarcomere,with its coordinated actin thin filaments and myosin thick filaments. For a muscle cell to contract, the sarcomere must shorten in response to a nerve impulse. The thick and thin filaments do not shorten, but they slide by one another, causing the sarcomere to shorten while the filaments remain the same length. This process is known as the sliding filament model of muscle contraction. The mechanism of contraction is accomplished by the binding of myosin to actin, resulting in the formation of cross-bridges that generate filament movement.

When a sarcomere shortens, some regions shorten while others remain the same length. A sarcomere is defined as the distance between two consecutive Z discs or Z lines. When a muscle contracts, the distance between the Z discs is reduced. The H zone, the central region of the A zone, contains only thick filaments and shortens during contraction. The I band contains only thin filaments and also shortens. The A band does not shorten; it remains the same length, but A bands of adjacent sarcomeres move closer together during contraction. Thin filaments are pulled by the thick filaments towards the center of the sarcomere until the Z discs approach the thick filaments. The zone of overlap, where thin filaments and thick filaments occupy the same area, increases as the thin filaments move inward.

The ideal length of a sarcomere to produce maximal tension occurs when all of the thick and thin filaments overlap. If a sarcomere is stretched past this ideal length, some of the myosin heads in the thick filaments are not in contact with the actin in the thin filaments, and fewer cross-bridges can form. This results in fewer myosin heads pulling on actin, and less tension is produced. If a sarcomere is shortened, the zone of overlap is reduced as the thin filaments reach the H zone, which is composed of myosin tails. Because myosin heads form cross-bridges, actin will not bind to myosin in this zone, again reducing the tension produced by the muscle. If further shortening of the sarcomere occurs, thin filaments begin to overlap with each other, further reducing cross-bridge formation and the amount of tension produced. If the muscle were stretched to the point where thick and thin filaments do not overlap at all, no cross-bridges are formed, and no tension is produced. This amount of stretching does not usually occur, as accessory proteins and connective tissue oppose extreme stretching.

With large numbers of relatively weak molecular motors, we can more easily adjust the force to meet our needs. Otherwise, we would regularly be producing too little or too much force for most of our tasks. Also, molecules are only capable of generating small forces based on their molecular structure.

You have already learned about how the information from a neuron ultimately leads to a muscle cell contraction.

Revisit previous material for a review of neuromuscular junctions.

One action potential in a motor neuron produces one contraction. This contraction is called a twitch. We think of "muscle twitches" as spasms that we can’t control, but in physiology, a twitch is a technical term describing a muscle response to stimulation. A single twitch does not produce any significant muscle contraction. Multiple action potentials (repeated stimulation) are needed to produce a muscle contraction that can produce work.

A twitch can last from a few milliseconds up to 100 milliseconds, depending on the muscle type. The tension produced by a single twitch can be measured by a myogram, which produces a graph illustrating the amount of tension produced over time. When combined with a plot of electrical signaling, the myogram shows three phases that each twitch undergoes. The first period is the latent period, during which the action potential is being propagated along the membrane and Ca²⁺ ions are released from the sarcoplasmic reticulum (SR). No tension or contraction is produced at this point, but the conditions for contraction are being established. This is the phase during which excitation and contraction are being coupled but contraction has yet to occur. The contraction phase occurs after the latent period when calcium is being used to trigger cross-bridge formation. This period lasts from the beginning of contraction to the point of peak tension. The last phase is the relaxation phase, when tension decreases as contraction stops. Calcium is pumped out of the sarcoplasm, back into the SR, and cross-bridge cycling stops. The muscle returns to a resting state. There is a very short refractory period after the relaxation phase (Review the previous material about the physiology of a neuromuscular junction)

A single twitch does not produce any significant muscle activity in a living body. Normal muscle contraction is more sustained, and it can be modified to produce varying amounts of force. This is called a graded muscle response. The tension produced in a skeletal muscle is a function of both the frequency of neural stimulation and the number of motor neurons involved.

The rate at which a motor neuron delivers action potentials affects the contraction produced in a muscle cell. If a muscle cell is stimulated while a previous twitch is still occurring, the second twitch will not have the same strength as the first; it will be stronger. This effect is called summation, or wave summation, because the effects of successive neural stimuli are summed, or added together. This occurs because the second stimulus releases more Ca²⁺ ions, which become available while the muscle is still contracting from the first stimulus (the first wave of calcium ions released). This allows for more cross-bridge formation and greater contraction. Because the second stimulus has to arrive before the first twitch has completed, the frequency of stimulus determines whether summation occurs or not.

If the frequency of stimulation increases to the point at which each successive stimulus sums with the force generated from the previous stimulus, muscle tension continues to rise until the tension generated reaches a peak point. The tension at this point is about three to four times higher than the tension of a single twitch; this is referred to as incomplete tetanus. Tetanus is defined as continuous fused contraction. During incomplete tetanus, the muscle goes through quick cycles of contraction with a short relaxation phase. If the stimulus frequency is so high that the relaxation phase disappears completely, contractions become continuous in a process called complete tetanus. This occurs when Ca²⁺ concentrations in the sarcoplasm reach a point at which contractions can continue uninterrupted. This contraction continues until the muscle fatigues and can no longer produce tension.

This type of tetanus is not the same as the disease of the same name that is distinguished by severe sustained contraction of skeletal muscles. The disease, which can be fatal if left untreated, is caused by the bacterium Clostridium tetani, which is present in most environments. The toxin from the bacterium affects how motor neurons communicate and control muscle contractions, resulting in muscle spasms or sustained contractions, also known as “lockjaw.”

Slightly different from incomplete tetanus is the phenomenon of treppe. Treppe (from the German term for step, referring to stepwise increases in contraction) is a condition in which successive stimuli produce a greater amount of tension, even though tension goes back to the resting state between stimuli (in tetanus, tension does not decrease to the resting state between stimuli). Treppe is similar to tetanus in that the first twitch releases calcium into the sarcoplasm, some of which will not be taken back up before the next contraction. Each stimulus afterward releases more calcium, but there is still some calcium present in the sarcoplasm from the previous stimulus. This extra calcium permits more cross-bridge formation and greater contraction with each additional stimulus up to the point where added calcium cannot be utilized. At this point, successive stimuli will produce a uniform amount of tension.

The strength of contractions is controlled not only by the frequency of stimuli but also by the number of motor units involved in a contraction. A motor unit is defined as a single motor neuron and the corresponding muscle fibers it controls. Increasing the frequency of neural stimulation can increase the tension produced by a single motor unit, but this can only produce a limited amount of tension in a skeletal muscle. To produce more tension in an entire skeletal muscle, the number of motor units involved in contraction must be increased. This process is called recruitment.

The size of motor units varies with the sizes of muscle. Small muscles contain smaller motor units and are most useful for fine motor movements. Larger muscles tend to have larger motor units because they are generally not involved in fine control. Even within a muscle, motor units vary in size. Generally, when a muscle contracts, small motor units will be the first ones recruited in a muscle, with larger motor units added as more force is needed.

All of the motor units in a muscle can be active simultaneously, producing a very powerful contraction. This cannot last for very long because of the energy requirements of muscle contraction. To prevent complete muscle fatigue, typically motor units in a given muscle are not all simultaneously active, but instead, some motor units rest, while others are active, allowing for longer muscle contractions by the muscle as a whole.

The action potentials produced by pacemaker cells in cardiac muscle are longer than those produced by motor neurons that stimulate skeletal muscle contraction. Thus, cardiac contractions are approximately ten times longer than skeletal muscle contractions. Because of long refractory periods, new action potential cannot reach a cardiac muscle cell before it has entered the relaxation phase, meaning that the sustained contractions of tetanus are impossible. If tetanus were to occur, the heart would not beat regularly, interrupting the flow of blood through the body.

Muscle contractions are among the largest energy-consuming processes in the body, which is not surprising considering the work that muscles constantly do. Skeletal muscles move the body in obvious ways such as walking and in less noticeable ways such as facilitating respiration. The structure of muscle cells at the microscopic level allows them to convert the chemical energy found in ATP into the mechanical energy of movement. The proteins actin and myosin play large roles in producing this movement.

Skeletal Muscle Fiber Types

There are three main types of skeletal muscle fibers (cells): slow oxidative (SO), which primarily uses aerobic respiration; fast oxidative (FO), which is an intermediate between slow oxidative and fast glycolytic fibers; and fast glycolytic (FG), which primarily uses anaerobic glycolysis. Fibers are defined as slow or fast based on how quickly they contract. The speed of contraction is dependent on how quickly the ATPase of myosin can hydrolyse ATP to produce cross-bridge action. Fast fibers hydrolyse ATP approximately twice as quickly as slow fibers, resulting in quicker cross-bridge cycling. The primary metabolic pathway used determines whether a fiber is oxidative or glycolytic. If a fiber primarily produces ATP through aerobic pathways, it is oxidative. Glycolytic fibers primarily create ATP through anaerobic glycolysis.

Since SO fibers function for long periods without fatigue, they are used to maintain posture, producing isometric contractions useful for stabilizing bones and joints, and making small movements that happen often but do not require large amounts of energy. They do not produce high tension, so they are not used for powerful, fast movements that require high amounts of energy and rapid cross-bridge cycling.

FO fibers are sometimes called intermediate fibers because they possess characteristics that are intermediate between fast fibers and slow fibers. They produce ATP relatively quickly, more quickly than SO fibers, and thus can produce relatively high amounts of tension. They are oxidative because they produce ATP aerobically, possess high numbers of mitochondria, and do not fatigue quickly. FO fibers do not possess significant myoglobin, giving them a lighter color than the red SO fibers. FO fibers are used primarily for movements, such as walking, that require more energy than postural control but less energy than an explosive movement such as sprinting. FO fibers are useful for this type of movement because they produce more tension than SO fibers and they are more fatigue-resistant than FG fibers.

FG fibers primarily use anaerobic glycolysis as their ATP source. They have a large diameter and possess high amounts of glycogen, which is used in glycolysis to generate ATP quickly; thus, they produce high levels of tension. Because they do not primarily use aerobic metabolism, they do not possess substantial numbers of mitochondria nor large amounts of myoglobin and therefore have a white color. FG fibers are used to produce rapid, forceful contractions to make quick, powerful movements. However, these fibers fatigue quickly, permitting them to only be used for short periods.

Most muscles (organs) possess a mixture of each fiber (cell) type. The predominant fiber type in a muscle is determined by the primary function of the muscle. Large muscles used for powerful movements contain more fast fibers than slow fibers. As such, different muscles have different speeds and different abilities to maintain contraction over time. The proportion of these different kinds of muscle fibers will vary among different people and can change within a person with conditioning.

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Skeletal muscles contribute to maintaining temperature homeostasis in the body by generating heat. Muscle contraction requires energy and produces heat as a byproduct of metabolism. All types of muscle produce heat, but because of the large amount of skeletal muscle present in the body, skeletal muscle contributes most greatly to heat production. This is very noticeable during exercise, when sustained muscle movement causes body temperature to rise. In cases of extreme cold, shivering produces random skeletal muscle contractions to generate heat as part of the negative feedback mechanism of maintaining body temperature.

Physical training alters the appearance of skeletal muscles and can produce changes in muscle performance. Conversely, a lack of use can result in decreased performance and muscle appearance. As you learned earlier, mature muscle cells grow from hypertrophy, not cell division. The loss of structural proteins and muscle mass occurs during atrophy. Cellular components of muscles can also undergo changes in response to changes in muscle use.

Slow fibers are predominantly used in endurance exercises that require little force but involve numerous repetitions. The aerobic metabolism used by slow-twitch fibers allows them to maintain contractions over long periods. Endurance training modifies these slow fibers to make them even more efficient by producing more mitochondria to enable more aerobic metabolism and more ATP production. Endurance exercise can also increase the amount of myoglobin in a cell, as increased aerobic respiration increases the need for oxygen. Myoglobin is found in the sarcoplasm and stores oxygen. Endurance training can also trigger the formation of more extensive capillary networks around the fiber, a process called angiogenesis, to supply oxygen and remove metabolic waste. To allow these capillary networks to supply the deep portions of the muscle, muscle mass does not greatly increase, maintaining a shorter distance for the diffusion of nutrients and gases. All of these cellular changes result in the ability to sustain low levels of muscle contraction for greater periods of time without fatiguing.

As discussed previously, there are a number of proteins that are important in regulating and carrying out the contractile process. Thus there are genetic disorders that lead to altered protein formation and dysfunction of the muscular system. Such dysfunction tends to affect many body systems, of which the respiratory system may be most important. Without the ability to appropriately contract the skeletal muscles of respiration, people cannot live very long. The skeletal muscular system is also very dependent upon a constant supply of ATP. Like many other systems, this requires the intracellular pathways to convert glucose into energy.

Think of all of the activities you do that require function of your muscular system. These include walking, chewing, swallowing, breathing, talking, etc. Dysfunctions of this system (such as weakness or hypertonia) can prevent the body from carrying out any of these activities normally. This in turn can affect many other systems. For example, if we can’t bring in appropriate nutrients and oxygen, every other system in the body would be affected, as they are all dependent on fuel sources.

Muscles require a large amount of energy and thus require a constant supply of oxygen and nutrients. Blood vessels enter muscle at its surface, after which they are distributed through the entire muscle. Blood vessels are found in the connective tissue that surrounds muscles, allowing oxygen and nutrients to be supplied to muscle and metabolic waste to be removed. The epimysium houses the arteries and veins that allow blood to enter and exit muscle. The blood vessels then branch into the epimysium to serve each fascicle and then further branch in the endomysium to form a capillary network that contacts each muscle fiber. The flexible, extensively branched capillary networks are able to withstand muscle contractions without being damaged.

Skeletal muscles are under neural control, which means that nerves must be present for the muscle to function. The epimysium contains nerve fibers that branch through the perimysium and epimysium to connect neurons to individual muscle fibers.

Although this unit has primarily focused on skeletal muscle, don't forget about cardiac and smooth muscle, both of which play vital roles in the cardiovascular system (and smooth muscle in other systems as well). Your heart needs to continuously contract in order to keep blood flowing to your organs, and in turn, supply them with needed oxygen and nutrients. But smooth muscle also plays a vital role. It is found in the walls of all blood vessels except for capillaries, and its function is to dilate or constrict, depending on the needs of the body and the downstream tissues. For example, if the skeletal muscles in your legs increase their metabolic rate because you start running, smooth muscle cells in the arteries feeding these muscles will relax. This dilates these arteries, allowing for a greater blood flow to the muscles of the legs. In fact, arteries to other regions (such as the gastrointestinal tract) may partially constrict in an effort to shunt more blood toward the legs. It is these smooth muscles that play a vital role in sending higher amounts of blood to where it is needed most. Skeletal muscles also play a role within the cardiovascular system. The heart acts as the pump to move blood out to the body cells, but the skeletal muscles assist with the movement of blood back to the heart. Because of valves in the veins that prevent back flow, the contraction of skeletal muscles around the major veins helps move the blood from one compartment to the next, slowly returning blood back to the heart.

Muscles are extremely important in the digestive system as well. The muscles of our mouth, tongue and jaw are responsible for biting and chewing our food. Within our digestive tract, sphincters located throughout the digestive system are responsible for compartmentalizing the digestive processes within discrete organs. We are most familiar with the anal sphincter that we are able to control to excrete waste from the digestive system. Also, throughout the digestive system, smooth muscle helps generate small forces to mix food in the stomach and help maintain movements throughout the digestive process.

The integumentary system is one of the main protective systems of the human body. It’s not a commonly known system. It contains your skin, hair, nails, and several glands. Did you know your skin is the largest organ in your body? It makes up approximately 7% of your body weight! The skin is also known as your integument or covering. Have you ever heard the expression that “beauty is only skin deep”? It’s an interesting statement because everything you see on another person’s appearance is dead! The layer of skin and hairs that are visible are actually dead epithelial cells!

The skin is actually formed from two layers: the superficial epidermis layer which is composed of epithelial tissue and the deeper connective tissue layer known as the dermis. The hypodermis is below the dermis and composed of loose connective tissue. When you give a subcutaneous (or sub-Q) injection you inject the drug into the hypodermis layer. Subcutaneous means below the cutaneous membrane which is another term for your skin. One medication commonly given via this method is insulin.

Let’s test your knowledge on some common facts and myths of the integumentary system.

Let’s check out the integumentary system in action in the following case study.

You and your friend, Tori, are baking cookies. It’s the end of the semester and you both have been craving chocolate chip goodness. While the cookies are in the oven, you and Tori decide to study your anatomy and physiology. You are currently studying the integumentary system. The timer goes off and Tori jumps up, very excited, grabs a dish towel and pulls the cookie sheet out of the over. “OW!” Tori yells – as she drops the cookie sheet onto the table. “I just burned my hand on the cookie sheet”.

You reply, “Quick, rinse it under cold water, I think that is supposed to stop the burn.”

“It really hurts!” Tori exclaims while running her hand under the cool water from the faucet.

“Let me see your hand” you tell Tori.

When she shows you, you notice a couple blisters beginning to form on her fingers and palm. “I think you burned through your epidermis layer and maybe to the dermis. Don’t blisters mean you have a second degree burn?” you ask her.

“What does that mean?” Tori asks. “Should I go to that prompt care place?”

“Let’s look it up, I think if you keep it clean you will be ok. There are several layers of cells in the epidermis, aren’t there?” you ask. “Our textbook says if the skin blisters it is a sign of a second degree burn. These burns don’t typically damage the lower layer, the dermis.”

“It’s a good thing it didn’t burn through the dermis, then I would be more prone to other infections, wouldn’t I? Didn’t we read about the skin protecting us from microbes around us?” Tori asks?

The integumentary system is vital for our body’s homeostasis. As we saw with Tori, the skin is an important barrier for protection. If the skin is damaged from a burn, or torn, it opens up an entry point for microbes to enter our body. This is why we always wear protective gloves when handling body fluids. The gloves protect us in case there are any openings in our skin. It’s better to be extra cautious about this. Our epidermis is multi-layered to make it better suited for protection. If Tori’s burn had penetrated deeper it also would have increased fluid loss and dehydration. The skin functions as a cover to keep interstitial fluids inside rather than seeping out. Every day we lose a small amount of water through our skin and our lungs from breathing. This water loss is termed insensible perspiration and is accelerated when in dry air. Our cells in the epidermis produce a protein known as keratin that helps to decrease water loss from our skin. If skin becomes dry, it cracks and creates an opening in our defenses. When you think of maintaining homeostasis, protection is probably one of the first processes you think of and the skin is vital for this.

The integumentary system is also crucial for body temperature regulation. When we are too warm, blood vessels going to the skin open up (vasodilate) and more blood flows to the surface of the skin to release heat to cool the body. Our skin turns pink or red when this happens. If body temperature continues to rise, our sweat glands become active and we sweat to cool off (this is termed sensible perspiration). When we are cold, the blood vessels shrink (vasoconstrict) to decrease blood flow, and consequently heat loss, from our skin. Our skin might turn blue from the decrease in blood flow. We also have a layer of body hair covering our body which insulates and helps us retain heat. It’s a good idea to wear a hat when in cold weather to reduce heat loss from our head!

Another function of the skin, isn’t commonly known. The skin produces vitamin D in response to sunlight or UV radiation. Vitamin D is a very important vitamin, it’s crucial for calcium absorption from our food, and has recently been shown to have anti-cancer properties. If our vitamin D levels fall, this could impact our skeletal system by decreasing the absorption of calcium, and consequently the amount that gets to our bones.

Our skin is also tied into our nervous system. One of our main senses – touch is dependent on numerous receptors located in our skin. We can feel and process information regarding pressure, temperature, light touch, and pain through our skin. If Tori didn’t feel pain when she touched the hot cookie sheet, she wouldn’t have dropped it to reduce the damage from the heat.

Clearly, the integumentary system is more involved in our functioning than a clear skin and gorgeous hair!

The integumentary system is composed not only of the skin, but also nails, glands, and hair. The most numerous component of the integumentary system is the integument or skin. The skin contains the superficial epidermis, which consists of epithelial tissue, and the deeper dermis which is formed from dense irregular connective tissue. The epidermis contains nerve endings for pain, which is why Tori felt the pain of the burn. The epidermis is avascular, which means it doesn’t have blood capillaries. Nutrients get to the epidermis from the vascular dermal layer. Only those cells closest to the dermis are able to receive the nutrients and these cells have rapid mitotic rates. The cells in the epidermis migrate to the surface, and then are shed daily. They are constantly being replaced by the cells deeper. The dermis contains the blood vessels, sweat and oil glands. The dermis also has receptors for touch. Below the dermis is the hypodermis layer. This is the fatty layer that anchors the skin to your body. The hypodermis is technically not part of the integumentary system.

The skin also contains sweat and oil (sebaceous) glands. Sweat glands release sensible perspiration to cool us when we overheat. Sweat is mostly water but also contains electrolytes and a waste product known as urea. Urea is one of the main components of urine too! Sebaceous glands produce oil, otherwise known as sebum. Sebum and sweat form a chemical barrier on our skin to decrease bacterial growth on our skin.

Hair and nails are additional structures associated with the integumentary system. Body hair takes up space to compete with pathogens for room on our skin. Body hair also insulates us. Did you know that there are approximately 100,000 hairs on your head and 30,000 in a man’s beard? Fingernails and toenails provide leverage and protection when we grab and manipulate objects.

The epidermis contains the pigment melanin, which protects our cells from UV radiation. Melanin is also responsible for our hair, skin and eye color. Keratin was previously mentioned and is important for decreasing water loss from our skin. Many skin lotions contain keratin to prevent dry skin. Another important protein is collagen. Collagen provides strength to our skin. Collagen has a white appearance and often when the skin heals extra collagen is placed at the site. Sometimes this results in a white scar.

When you study the integumentary system, you will learn about the chemical and cellular components which work together to maintain the integrity of the system. As consumers, we spend a lot of money on products meant to make our skin and hair look better, younger, and healthier. As you read through this topic, think about whether those products really can make a difference or if they are just the result of well-played marketing campaigns!

The skin is made up of two mutually dependent layers that are distinguished based on their structure and location. These layers – the epidermis and the dermis – contain a variety of structures, including blood vessels, hair follicles, and sweat glands. Beneath the dermis lies the hypodermis (subcutis). It is composed mainly of fatty tissue.

The most superficial layer, the epidermis, is composed of stratified squamous epithelia that are keratinized at the outermost surface, melanocytes, immune cells (Langerhans that modulate immune response) and sensory receptors (Merkel cells that detect light touch). The function of the epidermis layer is "protection." The keratinocytes and immune cells help protect the skin.

The dermis lies beneath the epidermis and is composed of two layers of connective tissue: a loose layer (papillary) and a dense irregular layer (reticular). Both layers of the dermis contain connective tissue components (collagen, elastin, fibroblasts), plus blood vessels, sensory receptors and lymphatics. The dermis is a "functional" layer. The dermis is connective tissue that can stretch and retract because of the strong and elastic extracellular matrix. The dermis also contains nerves.

Beneath these two layers lies the hypodermis, composed of loose connective tissue (adipose and areolar). The hypodermis is the "connection" layer. It connects the integument (epidermis and dermis) to organs and muscles in the body. This layer contains adipose tissue and connective tissue as well as blood vessels, nerves and immune cells.

The levels of organization of the skin and its accessory structures are listed below. You will be exploring these further in the coming pages.

• Molecular level – keratin, melanin and vitamin D
• Microscopic level – stem cells and skin cells
• Tissue level – epithelial and connective tissue
• Organ level – skin, consisting of the epidermis, dermis, and hypodermis, as well as hair, nails and glands

The epidermal layer of human skin synthesizes the precursor to vitamin D when exposed to UV radiation. In the presence of sunlight, an isomer of vitamin D₃, cholecalciferol, is synthesized from a derivative of the steroid cholesterol in the skin. The liver converts cholecalciferol to calcidiol, which is then converted to calcitriol (the active chemical form of the vitamin) in the kidneys. Vitamin D, which is really a hormone, is essential for normal absorption of calcium and phosphorous, which are required for healthy bones. In the present day, this hormone is added as a supplement to many foods including milk and orange juice, compensating for the need for sun exposure.

In addition to affecting bone health, Vitamin D is essential for general immunity against bacterial, viral and fungal infections. Recent studies are also finding a link between insufficient vitamin D and cancer.

Example

Rickets

Rickets is a disease of bone deterioration often caused by insufficient vitamin D, leading to insufficient calcium absorption. Children are especially prone to effects from this vitamin deficiency due to their rapid bone turnover and formation. In adults, the deficiency of vitamin D is called osteomalacia. Typically rickets is found in developing countries where malnutrition would prevent proper supply of calcium and dietary vitamin D.

The epidermis (or epithelial layer) is stratified squamous epithelia, composed of four to five layers (depending on body region) of epithelial cells. The top layers of the epidermis are made up of keratinocytes, which are cells containing the protein keratin. The keratinocytes on the most superficial layer of the epidermis are dead, and periodically slough away, being replaced by cells from the deeper layers. As keratinocytes move superficially from the deeper layers, they lose cytoplasm and become flattened, allowing for many layers in a relatively small space.

Basal cells are an example of tissue-specific stem cells, meaning they can turn into a variety of cell types found in that tissue. Under normal conditions, daughter basal cells most commonly replace lost keratinocytes.

The deepest layer of the epidermis and the most superficial layer of the dermis give out projections that interlock with each other (like Velcro) and strengthen the bond between the epidermis and the dermis. The projections originating in epithelial cells of the bottom layer of the epidermis are called desmosomes, and the ones originating in the dermis are called dermal papillae. Think of the projections as a formation of folds of cellular matter. The greater the fold, the stronger the connections made.

Merkel cells are sensory receptors that detect light touch. They form synaptic connections with sensory nerves that carry touch information to the brain. These cells are abundant on the surface of the hands and feet.

Melanocytes are cells in the bottom layer of epidermis that produce the pigment melanin, which gives hair and skin its color. Individuals whose melanocytes produce more melanin have darker skin color. Cellular extensions of the melanocytes reach up in between the keratinocytes.

Dendritic or Langerhans cells are tissue macrophages that contribute to the immune function of the skin. They engulf foreign organisms and signal to the immune system. Since the skin is in constant contact with the environment, it is important to have immune cells to help destroy any pathogens that might get past the cell barrier of the epidermis.

Cancer in general is initiated because of DNA damage that accumulates in a particular cell over time. Exposure to UV rays from the sun can ultimately lead to mutations in the genomes of various skin cells. Accumulation of genetic mutations over a period of time, in addition to other possible causes, can trigger cells to grow out of control. The normal signals that control cell divisions (even stem cells have these controls) are lost, and cells grow to form a tumor, or mass of cells. While some tumors are benign (stay in one place), some produce cells that dislodge from the tumor and establish tumors in other areas of the body. In other words, they metastasize and form secondary tumors.

Of skin cancers, about 80 percent are basal cell carcinoma, 16 percent are squamous cell carcinoma, and four percent are melanoma.

The skin contains many tissue types. The epidermis is classified as epithelial tissue composed of stratified squamous epithelia. The dermis is made of different types of connective tissues including areolar and dense irregular connective tissue, and histiocytes (tissue macrophages). The hypodermis contains areolar connective tissue, adipose tissue, and glands.

The epidermis is mainly made up of stratified (layered) squamous (flat) epithelial cells. Epithelial cells found in the different layers of the epidermis have different shapes. Stratification (layering) is important in the epithelial tissue of the integumentary system, which forms a barrier. Epithelial cells found in other systems have other surface cell shapes, including cube-like (cuboid) and column-like (columnar) in a single layer (simple) or multiple cell layers (stratified).

The epidermis contains several cell types of different origins, including keratinocytes (95 percent of the cells are keratinocytes), melanocytes, Langerhans cells and Merkel cells. The epidermis does not contain blood vessels or nerves, but Merkel cells provide signals to the sensory neurons below this layer in the dermis. Since there are no blood vessels, living cells of the epidermis are nourished by diffusion from the capillaries of the dermal papillae below.

While the epidermis is composed of epithelial cells, the dermis is composed of connective tissue. The dermis connects the epidermis to the hypodermis and provides structure and elasticity from collagen and elastin fibers. These proteins are made by fibroblasts found in the dermis. Collagen and elastin work together: collagens provide strength; elastins, as the name implies, are elastic and allow for distension. The skin must remain strong to protect you from abrasions and other cuts. However, the skin also needs to be able to deform and, hopefully, return to its original shape.

Skin contains different types of melanin, including pheomelanin, which is reddish, and eumelanin, which is dark brown. The amount and types of melanin produced is under genetic control. The combinations of the different types of melanin result in the wide range of skin colors and tones seen in humans. While the number of melanocytes do not vary too much between individuals, the skin tone depends on the amount and type of melanin produced by these cells. If a person has more eumelanin producing melanocytes, that person would have darker skin color. The predominance of pheomelanin is responsible for the reddish coloration of hair in some individuals.

Exposure to the sun causes melanin to build up, because sun exposure stimulates keratinocytes to secrete a peptide hormone that in turn stimulates melanocytes into producing melanin. The melanocytes produce and then transfer the melanin to keratinocytes. This buildup of melanin results in the darkening of the skin, or a tan. Increased melanin also protects the skin’s DNA from UV ray damage to some extent, although even very dark-skinned individuals can get skin cancer. Melanin synthesis does not peak until about 10 days after initial sun exposure, which is why pale-skinned individuals tend to suffer sunburns of the epidermis initially. Individuals with darker skin can also get sunburns, but are more protected than light-pigmented individuals.

Melanosomes, the cellular organelles that contain melanin, are temporary structures and are eventually destroyed by fusion with lysosomes, which makes tanning impermanent. Too much sun exposure can eventually lead to wrinkling of the skin due to destruction of the cellular structure of the skin, and in severe cases it can cause sufficient DNA damage to result in skin cancer. An uneven distribution of melanocytes in the skin results in the appearance of freckles.

The skin, the integumentary system's organ, is composed of the epidermis (epithelial tissue) and dermis (connective tissues), with an underlying hypodermis that is technically not part of the skin organ. Several layers of keratinocytes at the surface form the epidermis. The topmost layer is dead and sheds continuously. It is progressively replaced by stem cells that divide in the basal layer (stratum basale). The dermis connects the epidermis to the hypodermis and provides strength and elasticity due to the presence of collagen and elastin fibers. The hypodermis is the name for the layer of connective tissue that connects the dermis to the underlying organs. It also harbors adipose tissue for fat storage. Let's look at the structure and function of these parts of the skin organ in detail.

The epidermis (or epithelial layer) is made up of four or five distinct layers (strata), depending on the region of the body. From deep to superficial, they are named the stratum basale, stratum spinosum, stratum granulosum, stratum lucidum, and stratum corneum. The stratum lucidum is unique to areas like the palms of the hand (palmar surfaces) and soles of the feet (plantar surfaces), where the skin is thicker than it is in the rest of the body. The stratum basale is made up of the many cell types already discussed, including basal cells, melanocytes, Langerhans cells and Merkel cells. As you look at the more superficial layers, you see that they become mostly (or completely) composed of keratinocytes, which protect and waterproof the body. As the cells are pushed superficially (toward the surface) they make keratin. As the cells begin to fill with keratin, they become increasingly impervious to water, and it becomes more difficult for osmosis and diffusion to occur inside the cell. In addition, as cells enter each superficial layer (further away from the dermis, which contains the blood supply), the distance across which oxygen and other nutrients must diffuse increases, making it harder for the cells to get the nutrients they need. The keratinocytes in the stratum corneum (the most superficial layer) are usually inert, or dead, and periodically slough away, being replaced by cells from the deeper layers.

The thickness of thick skin is a function of the four upper layers of the epidermis: the stratum spinosum, stratum granulosum, stratum lucidum, and stratum corneum. The stratum corneum, consisting of keratin-packed dead cells, is substantially thicker in thick skin than in thin skin (more than 300 layers versus 15 layers of cells). The palms of your hands, soles of your feet, and your lips have thick skin. Thick skin is adapted to specialized activities, including gripping, walking and suckling, and the wear and tear that goes with those activities. Thick skin does not have hair, and has few glands.

Most of the rest of your skin is thin. The stratum lucidum isn’t even present in thin skin. The packed keratin provides most of the protective properties associated with the epidermis. Whereas the stratum corneum of thin skin may be completely shed and replaced in about a week, this replacement may take about a month in thick skin.

The skin's dermis is made up of two distinct layers of connective tissue. The papillary layer is made up of areolar connective tissue and the underlying reticular layer is composed of dense irregular connective tissue. This dermal part of the skin (organ) is vasculated (has blood vessels) and is innervated (has nerves). As described earlier, the dermis is sparsely populated with fibroblasts that produce collagen and elastin fibers in the extracellular matrix. This leads to a strong and elastic tissue structure. The matrix can also contain mast cells involved in allergic reactions.

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By NIST database (Fingerprint_Whorl). Public Domain

The hypodermis (also called the subcutis or subcutaneous layer) functions to connect the integument (epidermis and dermis) to the underlying muscles and organs. The hypodermis is not considered part of the skin, but has several important functions. Like the dermis, the hypodermis is made up of areolar tissue, collagen, and elastic fibers, providing it with some elasticity. Additionally, it contains adipose tissue, which functions as a mode of fat storage. The hypodermis is vascular and contains arteries, veins, and blood capillaries.

Adipose tissue present in the hypodermis accumulates fat, which serves as an energy reserve, insulates the body, and prevents heat loss. The fat distribution changes as our bodies mature and age. It is also hormone-dependent. Men tend to accumulate fat in different areas (neck, arms, lower back, and abdomen) than do women (breasts, hips, thighs, and buttocks). Physical inactivity due to a lack of exercise and sedentary jobs, combined with the consumption of high-calorie foods, has resulted in the highest rates of obesity ever seen in our country. While accumulation of fat provided an evolutionary advantage to our ancestors, who experienced unpredictable bouts of famine, it is now considered a major health threat. Improved diet and increased exercise are the best ways to control body fat accumulation, especially when it gets to levels that increase the risk of heart disease.

Accessory structures of the skin include hair, nails, sweat glands, and sebaceous glands. Although these structures appear to be part of the dermis, they are actually derived from the epidermis. The hair shaft is made of dead, keratinized cells and gets its color from melanin pigments. Nails are also keratinized and protect the extremities of our fingers and toes from mechanical damage. Sweat glands and sebaceous glands produce sweat and sebum, respectively. Each of these fluids has a role to play in maintaining homeostasis. Sweat helps the body remove excess fluids and electrolyte wastes and also cools down the body surface when it gets overheated. Sebum acts as a natural moisturizer of the dead, flaky outer keratin layer of skin and hair. Sebum is also known for its microbicidal and microbiostatic properties.

Hair is part of the integumentary system. Strands of hair originate from the base of the downward extension of living epithelial cells into the dermis that is called the hair follicle. Hair follicles are surrounded by the dermis, but the cells are part of the epidermis and are separated from the dermis by basal lamina layer. Hair forms in a manner similar to the skin: rapid division and differentiation of stem cells into keratinocytes that get pushed up and become flattened, dead, keratinized cells. The part of hair that is exposed on the skin surface is called the hair shaft, and the rest of the follicle is called the hair root. The bulge at the base of the hair root is called the hair bulb, which is made up of a layer of basal cells called the hair matrix. The hair matrix contains the cells that rapidly divide to form the hair. The hair bulb surrounds the hair papilla (made up of connective tissue, blood capillaries and nerve endings).

With permission from Jesus Lozano and Lorena Monarrez (172X10_hair_bulb_labelled)

With permission from Jesus Lozano and Lorena Monarrez (172-1x-Hair_follicle_labelled)

Just as the layers of the skin form on the inner layers and get pushed out to the surface as the dead skin on the surface sheds, basal cells in the center of the hair bulb divide to form layers of keratinocytes that form the medulla, cortex, and cuticle of the hair bulb. These layers are visible in a longitudinal section of the hair follicle. Keratin formation starts in the cells of the medulla and the keratin continues to be produced in the cortex and cuticle. Keratinization is completed as the cells are pushed to the skin surface to form the shaft of hair that is externally visible. The external hair is composed entirely of keratin.

Additionally, the hair follicle is made up of three concentric layers that make up the wall of the follicle — the internal root sheath, the external root sheath, and the glassy membrane. The cells of the internal root sheath are derived from the basal cells of the hair matrix. This layer does not surround the entire hair strand, but stops short at the base of the hair shaft. The external root sheath, which encloses the hair root, is made up of basal cells at the base of the hair root and tends to be more keratinous in the upper regions. The glassy membrane is a thick, clear connective tissue sheath covering the hair root and connecting it to the tissue of the dermis.

Hair serves a variety of functions. For example, hair on the head protects it from the sun and from heat loss; and hair in the nose and ears and around the eyes (eyelashes) defends the body by trapping dust particles that may contain allergens and microbes. Hair on the eyebrows prevents sweat and other particles from bothering the eyes. Hair also has a sensory function due to innervation of the hair papilla. Hair is extremely sensitive to changes in the environment, much more so than the skin surface. The hair root is connected to smooth muscles called arrector pili that contract in response to stimuli, making the external hair shaft “stand up.” This is visible in humans as goose bumps and even more obvious in animals, such as when a frightened cat’s fur puffs out. In many animals, the puffing out makes the animal appear larger, and could possibly enable it to scare off a predator. Another advantage of this ability to cause the hair to stand up is that it can trap air and can act as an insulator, decreasing heat loss.

Hairs grow during a phase called anagen, and they are eventually shed, only to be replaced by newer ones. When hair is naturally ready to be shed, the follicle becomes inactive during a phase called catagen. The follicle then becomes smaller, and becomes detached from the dermal papilla at the base, during the phase called telogen. The basal cells in the hair matrix then produce a new hair follicle during anagen. Hair typically grows at the rate of 0.3 mm per day and can continue growing for two to five years before being shed. About 50 hairs may be lost and replaced per day. Hair loss occurs if there is more hair shed than what is replaced, and it can happen due to hormonal or dietary changes.

Just like the skin, hair gets its color from the pigment melanin, produced by melanocytes in the hair matrix. Different hair color results from differences in the type of melanin, which is genetically determined. As a person ages, the melanin production decreases and hair tends to lose its color, becoming gray and/or white.

The nail is a specialized structure of the epidermis that occurs at the tips of our fingers and toes. The nail body is formed on the nail bed, and it is designed to protect the tips of our fingers and toes, as they are the farthest extremities and the parts of the body that experience the maximum mechanical stress. The epidermis in this part of the body has evolved a specialized structure upon which nails can form. The nail body forms at the nail root. Lateral nail folds, folds of skin that overlap the nail on its side, help anchor the nail body. The nail fold that meets the proximal end of the nail body forms the nail cuticle, also called the eponychium. The nail bed is rich in blood vessels, making it appear pink, except at the base, where there is a crescent-shaped region called the lunula. The nail body is composed of keratin-rich, densely packed dead keratinocytes. The area beneath the free edge of the nail, where debris gets lodged, is called the hyponychium.

In earlier sections, you learned about the amazing regenerative capacity of skin: Basal cells divide and differentiate to form keratinocytes, which move superficially to the surface and change their structure along the way. There are some cases where this regenerative property can cause problems, and some traumas where regeneration is put to the test.

Burns are wounds that result when the skin is exposed to intense heat, radiation, electrical current, or caustic chemicals. Burns cause skin cells to die, disrupting the epithelial barrier that normally prevents fluid loss. Depending on the severity of the burn, dehydration, electrolyte imbalance, and renal and circulatory failure may follow. Burn patients are treated with intravenous fluids to offset the dehydration, as well as intravenous nutrients that enable the body to repair tissues and replenish lost proteins. Another serious threat to a burn patient is the high possibility of infection. Burned skin is extremely susceptible to bacteria and other pathogens, as the loss of body covering provides a direct pathway for the entry of microorganisms.

Burns are classified by the degree of their severity. In first-degree burns, only the epidermis is damaged. Although painful, these burns typically heal on their own within a few days. A typical sunburn is a first-degree burn. Second-degree burns destroy both the epidermis and the dermis. They result in painful blistering of the skin. It is important for individuals with second-degree burns to keep the area clean and sterile in order to prevent infection. If this is done, the burns heal on their own within several weeks.

Third-degree burns are more serious and penetrate the full thickness of the skin, including the subcutaneous (hypodermis) layer. The skin may appear white, red, or black. Fourth-degree burns are the most severe, affecting the underlying muscle and bone as well. Third- and fourth-degree burns are usually not as painful because the nerve endings themselves are damaged. However, a third- or fourth-degree burn results in rapid water loss and infection due to the exposure of the underlying tissue, and requires emergency trauma care. Full-thickness burns cannot be repaired locally because the local repair machinery itself is damaged. Full-thickness burns require excision of the affected tissue (amputation in severe cases), followed by grafting of skin from an unaffected part of the body, or from skin grown in tissue culture for grafting purposes.

The integumentary system regulates body temperature through several different means. Recall that sweat glands — accessory structures to the skin — excrete water, salt, and other substances to cool the body when it becomes warm. This is termed "sensible perspiration." Even if the body does not appear to be noticeably sweating, approximately 500 mL of sweat are secreted a day. If the body becomes excessively warm due to high temperatures, vigorous activity, or a combination of the two, the blood vessels in the integumentary system dilate and sweat glands produce large amounts of sweat — up to three gallons a day. As the sweat evaporates from the skin surface, the body is cooled; in a way, the skin surface acts like the radiator of a car. The dilated blood vessels in the dermis that account for the redness that many people experience when exercising on a hot day also help in the dissipation of body heat by increasing the superficial blood flow.

When temperatures are cold, the adipose tissue of the hypodermis helps insulate the body. Goosebumps and the arrector pili muscles help to insulate by trapping air on the surface of the skin. Additionally, the dermal blood vessels constrict to decrease blood flow (and heat loss) at the skin.

The fact that you can feel an ant crawling on your skin, causing you to flick it off before it bites, is due to the fact that the sensory receptors in the skin (especially the hair root plexus associated with the hair in the follicles) can sense changes in the environment. This occurs via sensory receptors that convert physical or chemical stimuli into electrical signals that are sent to the central nervous system (CNS; brain and spinal cord). The CNS then processes this sensory input and generates a voluntary response to the ant. The skin acts as a sense organ because the dermis and hypodermis contain sensory receptors that extend into the epidermis. These receptors, such as Merkel discs, are more concentrated at the fingertips and lips, which are most sensitive to touch. Examples of other sensory receptors present in the skin are tactile (Meissner's) corpuscles and lamellated (Pacinian) corpuscles that respond to pressure and vibration, respectively, and free nerve endings that are sensitive to temperature (hot or cold) and pain.

The major function of the endocrine system is to participate in homeostatic feedback loops by acting as a means of communication between integrators and effectors, and sometimes acting as the sensor as well. Since the function of the endocrine system is to maintain homeostasis, there will be many system level examples at the end of this chapter. Also, this is an excellent time to review the concept and formal structure of homeostasis if you are uncertain or out of practice.

The endocrine system is also involved with growth, development and adaptation. Within all of these changing processes, our bodies tolerate fluctuations within certain limits but still overall homeostasis needs to be maintained.

The lipid-derived hormones include steroid hormones and eicosanoids. Steroid hormones, the primary class of lipid hormones in humans, are derived from cholesterol and show structural similarity to that molecule. Examples of steroid hormones include estrogen and testosterone, which are released by reproductive organs, and aldosterone and cortisol, which are released by the adrenal glands.

Steroid hormones are released as synthesized. They are insoluble in water, so to circulate through the blood they bind to transport proteins in serum. Since they are bound to carrier proteins, steroid hormones typically remain in circulation longer than other classes of hormones. Recall that the "lifetime" of a molecule from production to destruction is called the half-life. The steroid hormone cortisol has a half-life of 60 to 90 minutes, whereas epinephrine, an amino acid-derived hormone, has a half-life of approximately one minute. They are eventually degraded and excreted in urine or bile.

Biosynthetic pathways for some selected steroid hormones.

Eicosanoids are a class of signalling molecules derived from polyunsaturated fatty acids. They are typically released as paracrine signals upon stimulation and are only active for a few seconds.

Of the amino acid-derived hormones, some circulate for only a few minutes while others may circulate for days. The amino acid tyrosine is the precursor for two groups of hormones: the thyroid hormones, produced in the thyroid gland; and the catecholamines (epinephrine and norepinephrine), produced in the adrenal medullae. The amino acid tryptophan is the precursor for the hormone melatonin, secreted by the pineal gland, and the hormone serotonin, which is quite widespread in the body. Some of these hormones have a circulating half-life of a few days (thyroid hormones) while some are rapidly degraded (catecholamines).

Peptide hormones are short peptides and polypeptide chains. Recall that peptides are usually made up of fewer than 50 amino acids and proteins are typically longer than that. Some peptide hormones of longer lengths can have secondary structures. Protein hormones, being much longer than peptides, can have more extensive three-dimensional structures and can even be globular.

Peptide hormones are a diverse group and include molecules that are only a few amino acids, such as antidiuretic hormone and oxytocin (each with 9 amino acids), produced by the pituitary gland. This class also includes proteins, such as growth hormone (191 amino acids), and glycoproteins, such as follicle-stimulating hormone (92 amino acids with glycosylation). Peptide hormones can either be released as produced or stored and released in response to stimulus. Most are water soluble and are easily transported in blood plasma, but some also bind to transport proteins. Most have a half life of minutes.

Hormone production can be regulated by positive and negative feedback pathways. In positive feedback systems, the release of a hormone leads to an action that stimulates release of more of the same hormone.

In a hormonal negative feedback loop, when a stimulus causes the release of a hormone (Hormone A), the hormone binds to the target cell receptor, causing the necessary metabolic change toward homeostasis. In a negative loop, the effect of this metabolic change is to counter the stimulus that caused the release of Hormone A. Once the cause of the stimulus returns to normal range, the production of that hormone stops and plasma level of that hormone returns to the normal (pre-stimulus) level. In this way, the concentration of most hormones in blood is maintained within a narrow range.

There are three mechanisms by which endocrine glands are stimulated to synthesize and release hormones: humoral regulation, hormonal regulation, and neural regulation.

Steroid hormones are lipophilic and need transport proteins in the blood. Once released from their transport protein, the non-polar hormone is able to diffuse across the plasma membrane of cells. Recall that the lipid bilayer of the plasma membrane of cells uses amphiphilic phospholipids to compartmentalize the cytoplasm of a cell. When a steroid hormone crosses the plasma membrane of a target cell, it binds to an intracellular hormone receptor in the cytoplasm, on intracellular membrane system (ER) or, within the nucleus of the cell. The receptor/hormone complex can then bind to a specific site on DNA and act as a transcription regulator to increase or decrease the synthesis of particular mRNA molecules coded by these specific genes. This, in turn, alters mRNA production, which determines the amount of corresponding protein that is synthesized. The steroid hormone regulates specific cell processes. The rate of transcription and protein synthesis is directly proportional to the amount of hormone forming receptor/hormone complexes; so if the hormone production increases, so does the physiological effect in the body.

The thyroid hormones, T₃ and T₄, also use plasma transport proteins and intracellular DNA-binding receptors. There are, however, some important physiological differences with the steroid hormone mechanism. The target cells have membrane transport proteins that transport the thyroid hormones into the cell. The Thyroid hormone receptor is found bound to a transcription repressor protein on the DNA. The binding of the hormone with the receptor-repressor complex to form the receptor/hormone complex causes the repressor protein to dissociate, and a transctiption activator protein becomes associated with the receptor. This, in turn, initiates transcription.

Most peptide and amino acid hormones are polar and therefore cannot diffuse through the plasma membrane of cells. So, they bind to plasma membrane hormone receptors on the outer surface of the plasma membrane. Unlike steroid hormones, polar hormones also alter intracellular processes and can also affect the target cell’s transcription. Since they cannot enter the cell and act directly on any DNA-binding proteins, they exert their transcriptional effects through intermediate molecules called second messengers as described below. Catecholamines (amine class) and polar eicosanoids (lipid-derived class) also bind to cell-surface hormone receptors.

Binding of these hormones to a cell membrane surface receptor results in activation of a signaling pathway that triggers a cascade of intracellular activity and specific effects associated with the hormone. Most hormones that bind at the surface receptor remain outside the target cell. Some hormones are taken into the cell by endocytosis to initiate the intracellular biochemical response from within vesicles. The hormone that initiates the signaling pathway, the first messenger, activates a second messenger within the cell.

G-proteins are a class of trans-membrane cell surface proteins that can be activated by hormones or ions and other chemicals for cell signaling. G-proteins remain inactive unless a hormone is bound to its cell surface receptor. Inactive G-proteins are bound to GDP on its cytoplasmic side. When a hormone binds to the cell surface receptor the bound GDP is replaced by GTP.

Activated G-proteins can have different functions depending on the hormone receptor: it can open a membrane protein channel; it can release a small molecule; or it can activate a membrane-bound enzyme. There is a large variety of G-protein-induced effects. For example, G-protein-linked ion channels can stimulate movements of ions across the membranes. There are specific channels for potassium, sodium, calcium or chloride.

For G-protein activated membrane-bound enzymes, there are large numbers of activated enzymes. One of the membrane bound enzymes that the G-Protein coupled receptor (GPCR) activates upon binding to a hormone molecule is the adenylate cyclase. This enzyme catalyzes the conversion of ATP to cyclic AMP (cAMP). which, in turn, activates a class of enzymes called protein kinases. These kinases transfer a phosphate group from ATP to a substrate molecule in a process called phosphorylation. The phosphorylation of a substrate molecule changes its shape, thereby activating it. This chain of reactions, where hormone binding to the GPCR leads to the appearance of cAMP in the cytoplasm as the second messenger which, in turn, leads to the activation of protein kinase is an example of a “reaction cascade.” In this case, since a signal from the exterior of the cell is transferred to the interior via the formation of a “second messenger,” the process is called “signal transduction cascade." Other second messengers that can be involved as a result of hormone binding to a cell membrane receptor include cyclic GMP (derived from guanosine triphosphate), tyrosine kinases, inositol phospholipids, and even calcium ions. Cellular responses to hormone binding of a cell membrane receptor include altering membrane permeability, activating metabolic pathways, stimulating synthesis of proteins and enzymes, and hormone release.

The binding of a hormone at a single cell membrane receptor causes the activation of many G-proteins, which can catalyze many reactions simultaneously. Thus, the effect of a peptide hormone is amplified as the signaling cascade progresses. A small amount of hormone can trigger the formation of a large amount of cellular product. To stop hormone activity, the cascading chemical reaction is interrupted; for example cAMP is deactivated by the cytoplasmic enzyme phosphodiesterase (PDE). PDE is always present in the cell, and it breaks down cAMP spontaneously, preventing overproduction of cellular products. The specific response of a cell to a lipid-insoluble hormone depends on the type of receptors that are present on the cell membrane and the substrate molecules present in the cell cytoplasm.

The pituitary-hypothalamus axis links the nervous system with the endocrine system. The hypothalamus is a region of the brain that is located inferior to the thalamus. It coordinates signals from internal organs and other regions of the brain and regulates a response from the endocrine system via the pituitary. The hypothalamus secretes both releasing hormones that stimulate the anterior pituitary to secrete a hormone and inhibiting hormones that inhibit the release of a hormone from the anterior pituitary.

The pituitary gland is a pea-sized gland located at the base of the brain attached to the hypothalamus via a stalk called the infundibulum. The pituitary gland is primarily regulated by nerve impulses or hormones released by neurosecretory cells of the hypothalamus. The pituitary, in turn, releases hormones that either have a direct effect on target cells or regulate hormone production by other endocrine glands. Those hormones that control the release of another hormone from an endocrine gland are called tropic hormones. The pituitary has two distinct regions: the anterior pituitary, and the posterior pituitary. The anterior pituitary secretes seven different peptide or protein hormones: growth hormone(GH), prolactin (PRL), thyroid-stimulating hormone (TSH), adrenocorticotropic hormone (ATCH), follicle-stimulating hormone (FSH), luteinizing hormone (LH), and melanocyte stimulating hormone (MSH). The posterior pituitary is an extension of the brain and releases hormones produced by the hypothalamus. The posterior pituitary releases antidiuretic hormone (ADH) (also known as vasopressin) and oxytocin. The pituitary looks like one gland because the anterior and posterior pituitary do not have externally visible distinctions, but from a cell and tissue perspective, they are really two different and distinct organs.

The anterior pituitary gland, or adenohypophysis, is surrounded by a capillary network. This capillary network is a part of the hypophyseal portal system that carries substances from the hypothalamus directly to the anterior pituitary. Remember that substances such as hormones can only leave or enter the circulatory system at capillaries, and portal systems (portal systems are also found in the digestive system) move material from one capillary bed to another without returning it to the main circulation. Anterior pituitary hormones then enter the capillaries and travel to the heart and through the systemic system in the same way other hormones do.

Several anterior pituitary hormones (TSH, ACTH) are tropic hormones, because they control the functioning of other endocrine glands. While these hormones are produced by the anterior pituitary, their production is controlled by regulatory hormones produced by the hypothalamus. Negative feedback mechanisms regulate how much of these regulatory hormones is released, and how much anterior pituitary hormone is secreted.

The posterior pituitary is significantly different in structure and function from the anterior pituitary. As its name implies, the posterior pituitary is behind the anterior pituitary (toward the back). It contains mostly axons of secretory neurons and neuroglial cells; the cell bodies of these neurons are in the hypothalamus. The posterior pituitary and the infundibulum together are referred to as the neurohypophysis.

The posterior pituitary does not produce hormones, but stores hormones produced by the hypothalamus and releases them into the bloodstream. The hormones antidiuretic hormone (ADH) and oxytocin are produced by neurons in the hypothalamus and transported within these axons along the infundibulum to the posterior pituitary. They are released into the posterior pituitary capillaries in response to neural signaling from the hypothalamus. These hormones are considered to be posterior pituitary hormones, even though they are produced by the hypothalamus, because that is where they are released into the circulatory system.

The thyroid gland possesses two lobes that are connected by the isthmus. It is located in the neck, just below the larynx with the isthmus in front of and lobes lateral to the trachea. It has a dark red color due to its extensive vasculature. When the thyroid increases in size due to dysfunction, it can be felt under the skin of the neck. The main function of the thyroid gland is the synthesis and storage of thyroid hormones that are involved in maintaining metabolic homeostasis.

The thyroid gland is made up of many spherical thyroid follicles, which are lined with simple cuboidal epithelium. These follicles contain a viscous fluid called colloid that stores the glycoprotein thyroglobulin, the precursor to the two thyroid hormones. Thyroglobulin is not normally released into circulation unless the thyroid gland is damaged due to disease or injury. Other endocrine cells, called parafollicular cells, are located between adjacent follicles and produce a different hormone, calcitonin, that is involved in blood calcium homeostasis.

Unlike most endocrine glands, the thyroid gland stores large amounts of some of the hormones it synthesizes. Thyroglobulin is produced and secreted by follicle cells into the lumen of follicles as a colloid. There it undergoes post-translational modification to produce functioning thyroid hormones. Iodide molecules are added to the thyroglobulin precursor to produce the hormones thyroxine and triiodothyronine. Thyroxine is also known as T₄ because it contains four atoms of iodine, and triiodothyronine is also known as T₃ because it contains three atoms of iodine. In developed countries, the iodide required for hormone synthesis is obtained primarily from iodized salt. However, seafood and plants grown in iodine rich soil at lower elevations also provide the required iodide. Since iodine as a molecule is quite volatile, the food grown in higher elevations (lower atmospheric pressure) lacks sufficient iodine. Iodide ions are actively transported into the follicular lumen from the capillaries by follicle cells. Follicle cells are stimulated to release stored T₃ and T₄ from the lumen into the blood capillaries by thyroid stimulating hormone (TSH), which is produced by the anterior pituitary. Follicle cells also begin synthesizing more T₃ and T₄ in response to TSH stimulation.

A third hormone, calcitonin, is produced by parafollicular cells, or C cells of the thyroid. Calcitonin release is not controlled by TSH, but instead is released when calcium ion concentrations in the blood rise. Calcium ions bind to specific receptor on the C cell and stimulate release of calcitonin. Calcitonin acts primarily in children to lower blood calcium levels when levels get too high. Calcitonin causes decreased tubular reabsorption of Ca²⁺ in the kidneys, leading to calcium loss in urine. It inhibits bone resorption activity of osteoclasts and calcium absorption in intestine to also reduce plasma calcium levels. It is also suspected to have an indirect effect stimulating osteoblast activity and development. However, in adult humans it appears to play only a minor role in calcium homeostasis because abnormalities in calcitonin production do not appear to be associated with specific plasma calcium imbalances. Research has implicated its role during times of high calcium demands, such as pregnancy and lactation.

The four parathyroid glands are each the size of a grain of rice and are usually located on the posterior surface of the thyroid gland. The exact location and number of parathyroid glands can vary from person to person. The parathyroid glands are named for their proximity to the thyroid gland (para- means next to), often seeming to be part of the same gland; however, their cells are distinct from those of the thyroid gland.

Note that this image is on a different anatomical plane than the previous image of the thyroid.

Each parathyroid gland is covered by connective tissue and contains many secretory cells called chief cells, which synthesize and secrete parathyroid hormone (PTH). Another type of cell, oxyphil cells, can be distinguished histologically in the parathyroid but they are not clearly understood. They appear to increase during renal failure, but their function is still a subject of clinical research.

PTH is synthesized as a pro-peptide that is cleaved into an active hormone, which is vital in maintaining blood calcium levels. Calcium is required for nerve impulse transmission, for muscle contractions and for many cellular processes--including signal transduction. Therefore, plasma calcium concentrations must be maintained within a narrow normal range of 9–10 mg/dL. PTH functions by increasing blood calcium concentrations when calcium ion levels fall below normal. Calcium ions bind to specific receptors on the chief cell and inhibit release of PTH; when the plasma calcium level falls, PTH secretion is stimulated. PTH stimulates reabsorption of calcium from filtrate during urine formation, increased absorption in the intestines from digested products and increased activity of osteoclasts to release calcium (and phosphate) from bone matrix into the plasma. There is some evidence that it may also indirectly inhibit osteoblast activity.

A parathyroid adenoma is a benign tumor of the parathyroid gland that can cause an overproduction of PTH leading to hyperparathyroidism. Hyperparathyroidism results in hypercalcemia, which can lead to kidney stones. Additionally, increased rate of bone resorption due to higher osteoclast activity due to this condition may also lead to osteoporosis. Usually only one of the four parathyroid glands is affected and can be surgically removed without any adverse effects. However, removal of all the parathyroid glands will cause an imbalance in blood calcium levels resulting in death.

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The adrenal glands help regulate the body’s response to stress, controlling blood pressure, and maintaining the body’s water, sodium, and potassium levels. The adrenal glands are associated with the pair of kidneys which are retroperitoneal and lateral to the spinal column ; one gland is located on the superior surface of each kidney (hence they are also known as suprarenal glands). The adrenal glands consist of an outer adrenal cortex (cortex means outer layer) and an inner adrenal medulla (medulla means middle). Functionally and anatomically the adrenal gland is really two glands packaged together. The cells of the cortex are endocrine and those of the medulla are neurosecretory. The cells look very different and embryologically they come from different tissues. These regions secrete different hormones: the adrenal cortex produces steroid hormones, and the adrenal medulla produces catecholamine hormones.

The adrenal cortex is the outer layer of the adrenal gland and is made up of layers of epithelial cells and associated capillary networks. These layers form three distinct regions that secrete different steroid hormones: the outer zona glomerulosa produces mineralocorticoids (influence salt and water balance), the middle zona fasciculata produces glucocorticoids (impact metabolism and inflammation), and the inner zona reticularis produces androgens (regulate catabolism and sexual characteristics).

The main mineralocorticoid is aldosterone, which regulates the concentration of ions in urine, sweat, and saliva. Aldosterone release from the adrenal cortex can be triggered by a number of things including decrease in blood concentrations of sodium ions, blood volume, or blood pressure, or an increase in blood potassium levels.

The three main glucocorticoids are cortisol, corticosterone, and cortisone. The glucocorticoids stimulate the synthesis of glucose from non-glycogen sources, and they promote the release of fatty acids from adipose tissue. These hormones increase blood glucose levels to maintain levels within a normal range between meals. They are secreted in response to ACTH, and levels are regulated by negative feedback.

Androgens are a class of hormones and that affect sexual characteristics. Testosterone is associated with male sexual characteristics, while progesterone and estrogen are associated with female reproductive function; androstenedione is an intermediate molecule in the synthetic pathways of these and many of the steroid hormones.

The adrenal medulla is the inner layer of the adrenal glands and contains chromaffin cells, which are large, irregularly shaped cells that are closely associated with blood vessels. These cells are innervated by autonomic (involuntary) nerve fibers from the central nervous system, which allows for quick hormone release.

Chromaffin cells of the adrenal medulla produce epinephrine (adrenaline) and norepinephrine (noradrenaline). Epinephrine is the primary adrenal medulla hormone accounting for 75–80 percent of its secretions. Epinephrine and norepinephrine increase heart rate, breathing rate, cardiac muscle contractions, and blood glucose levels. They also accelerate the breakdown of glucose in skeletal muscles and stored fats in adipose tissue.

Both are stored in vesicles or granules in the adrenal medulla, very similar to the way posterior pituitary cells store the neurosecretory hormones from hypothalamus for release. The release of epinephrine and norepinephrine into the blood is stimulated by neural impulses from the sympathetic nervous system. These neural impulses originate from the hypothalamus in response to stress to prepare the body for the fight-or-flight response.

The pineal gland is located between the cerebral hemispheres of the brain. It is attached to the roof of the third ventricle in the diencephalon. The pineal gland consists of secretory cells, called pinealocytes, that secrete the hormone melatonin. Melatonin is derived from serotonin (a neuropeptide) and is regulated in response to the light and dark of the environment (the diurnal cycle). Photons, packets of light, are detected by the retinas of the eyes, which initiate a nerve impulse that is detected by the pineal gland. This mechanism is similar to the process in the posterior pituitary or adrenal medulla. The pineal gland synthesizes the highest levels of melatonin during the night, when light levels are the lowest, and the increased blood concentrations of melatonin makes us sleepy. Blood concentrations of melatonin are lowest during the day, when light exposure inhibits the synthesis of the hormone.

The target cells of melatonin are located in the suprachiasmatic nucleus (SCN) of the brain. The SCN functions as a biological clock that regulates physiological processes such as the sleep-wake cycle, appetite, and body temperature. Melatonin is thought to inhibit the release of gonadotropins from the anterior pituitary, which affect the onset of puberty.

Higher melatonin levels at night make us sleepy, and a disruption in melatonin synthesis can disrupt the sleep cycle. Travel across several time zones can result in disruptions to the sleep cycle, or jet lag. This is due to the change in the dark-light cycle that the body is accustomed to, and it can take several days for melatonin synthesis to adapt to the change. Melatonin supplements are available to treat jet lag as well as other sleep disorders; however, their efficacy has not been conclusively established.

The pancreas is an elongated organ that plays a central role in energy metabolism, storage, and utilization of glucose (carbohydrate). It is located slightly dorsal to the stomach and between the stomach and the small intestine. The tapered distal end lies in contact with the spleen, while the ducts from broader proximal end enter the duodenum at gastro-duodenal junction. The pancreas contains both exocrine cells that excrete digestive enzymes and endocrine cells that release hormones. Approximately 99 percent of pancreatic cells are exocrine cells that are arranged around ducts in clusters called acini (singular is acinus).

The endocrine cells of the pancreas form clusters called pancreatic islets or the islets of Langerhans (islets are small islands) with associated blood capillaries. The pancreatic islets contain two major cell types: alpha cells, which constitute 20 percent of the total mass of the islets and produce the hormone glucagon, and beta cells, which constitute 75 percent of the total mass of the islets and produce the hormone insulin. These hormones regulate blood glucose levels. Alpha cells release glucagon as blood glucose levels decline below the set point. When blood glucose levels rise, alpha cells stop secreting glucagon, and beta cells then release insulin. When blood glucose levels drop below the set point (which does not happen under normal conditions), beta cells stop secreting insulin.

Pancreatic cells also contain two minor populations of cells: delta cells, which constitute 4 percent of the total mass of the islets and secrete somatostatin, and F (or PP) cells, which constitute 1 percent of the total mass of the islets and secrete pancreatic polypeptide. They have specific paracrine regulator effects in the pancreas. Pancreatic polypeptide is secreted after a high protein meal or fasting and inhibits pancreatic exocrine secretion and stimulates gastric juice secretion (opposite effect of cholecystokinin, CCK, of the small intestine). It also stimulates both alpha and beta cells.

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The gonads, the male testes (sing. Testis) and female ovaries, function in production of gametes (sperm and ovum) and also produce steroid hormones. The testes produce androgens, testosterone being the most prominent. Testosterone stimulates the development of male secondary sex characteristics and the production of sperm cells. The testes also produce the hormone inhibin, which inhibits the release of the tropic hormone from the anterior pituitary follicle-stimulating hormone (FSH) needed for the development of sperm (spermatogenesis).

The ovaries produce the hormones estrogen and progesterone, which stimulate the development of female secondary sex characteristics, regulate the menstrual cycle, and prepare the body for childbirth. The ovaries also produce the hormone inhibin, which inhibits the release of FSH.

The placenta, which supplies the necessary nutrients to the fetus, is also an endocrine organ. It synthesizes and secretes a number of hormones that are crucial for the maintenance of pregnancy. The human chorionic gonadotropin hormone (hCG), that is the basis of urine pregnancy tests is another of the placental hormones. As the fetus develops, the placenta takes over the production of estrogen and progesterone to maintain pregnancy. The high level of estrogen facilitates the growth of the uterus and the mammary glands during gestation. Progesterone is important in suppressing maternal immune response towards the fetus and inhibiting uterine smooth muscle contraction. The placenta also produces relaxin, that affects collagen metabolism and softens the pubic symphysis to facilitate birthing. It also produces lactogen, which is structurally similar to prolactin and growth hormone (pituitary hormones), but its role, if any, in human lactation is still being investigated.

There are several organs whose primary functions are non-endocrine but that also possess endocrine functions. These include the heart, gastrointestinal tract, kidneys, adipose tissue, skin, and thymus.

Hormones have a wide range of effects and modulate many different body processes. The key processes that will be examined in this section are hormonal regulation of the excretory system, the reproductive system, metabolism, blood calcium concentrations, growth, and the stress response.

We will see how hormones help the body to maintain homeostasis, by integrating different organ systems.

Maintaining a proper water balance in the body is important to avoid dehydration or excess water. The water concentration of the body is monitored by osmoreceptors in the hypothalamus, which detect the concentration of electrolytes in the blood. The concentration of electrolytes in the blood rises when there is water loss due to excessive perspiration, inadequate water intake, or low blood volume due to blood loss. An increase in blood electrolyte levels results in a neural signal being sent from the osmoreceptors to the hypothalamus. The hypothalamus produces antidiuretic hormone (ADH), which is transported to, and released from, the posterior pituitary. It is also known as vasopressin. The target cells for ADH are the distal tubule cells in the kidneys, which are stimulated to absorb more water from urine, resulting in an increase in the water level of blood and making urine which is more concentrated.

Chronic underproduction of ADH results in diabetes insipidus. If the posterior pituitary does not release enough ADH, water cannot be retained by the kidneys and is eliminated in the urine. This causes increased thirst, but water taken in is lost again, and water must be continually consumed. If the condition is not severe, dehydration may not occur, but severe cases can lead to electrolyte imbalances due to dehydration.

Another hormone responsible for maintaining electrolyte concentrations in extracellular fluids is aldosterone, a steroid hormone that is produced by the adrenal cortex. In contrast to ADH, which promotes the reabsorption of water to maintain proper water balance, aldosterone maintains proper water balance by enhancing Na⁺ reabsorption from extracellular fluids. Because it affects the concentrations of minerals, Na⁺, aldosterone is referred to as a mineralocorticoid. Aldosterone release is stimulated by a decrease in blood sodium levels, blood volume, or blood pressure, or an increase in blood potassium levels. Aldosterone targets the renal tubules of the kidneys, where it causes the reabsorption of Na⁺ from urine and the secretion of K⁺ into the urine. It also prevents the loss of Na⁺ from sweat, saliva, and gastric juice. The reabsorption of Na⁺ also results in the osmotic reabsorption of water, which alters blood volume and blood pressure.

Aldosterone production can be stimulated by low blood pressure, which triggers a sequence of chemical releases. When blood pressure drops, cells in the juxtaglomerular apparatus of the kidney detect this and release renin. Renin circulates in the blood and reacts with a protein produced by the liver called angiotensinogen. When angiotensinogen is cleaved by renin, it produces angiotensin I, which is then converted into angiotensin II. Angiotensin II impacts water and Na⁺ reabsorption and causes the release of aldosterone by the adrenal cortex with a similar effect; ultimately these increase blood pressure. Angiotensin II also causes an increase in ADH and increased thirst, which both help to increase fluids and raise blood pressure.

Regulation of the reproductive system is a process that requires the action of hormones from the pituitary gland, the adrenal cortex, and the gonads. During puberty in both males and females, the hypothalamus produces gonadotropin-releasing hormone (GnRH), which stimulates the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the anterior pituitary. These hormones regulate the gonads (testes in males and ovaries in females) and therefore are called gonadotropins. In both males and females, FSH stimulates gamete production, and LH stimulates production of hormones by the gonads. An increase in gonad hormone levels inhibits GnRH production through a negative feedback loop.

Blood glucose levels vary widely over the course of a day as periods of food consumption alternate with periods of fasting. Insulin and glucagon are the two hormones that are primarily responsible for maintaining homeostasis of blood glucose levels. Additional regulation is mediated by the thyroid hormones.

Regulation of blood calcium concentration is important for proper muscle contractions and release of neurotransmitters. Calcium also affects voltage-gated plasma membrane ion channels, affecting nerve impulses and other cell physiology. If plasma calcium levels are too high, membrane permeability to sodium decreases and membranes become less responsive. If plasma calcium levels are too low, membrane permeability to sodium increases and convulsions or muscle spasms can result.

Blood calcium levels are regulated by parathyroid hormone (PTH), which is produced by the parathyroid glands. PTH is released in response to low blood Ca²⁺ levels. PTH increases Ca²⁺ levels by targeting the skeleton, the kidneys, and the intestine. In the skeleton, PTH stimulates osteoclasts, causing bone to be broken down and releasing Ca²⁺ from bone into the blood. PTH also inhibits osteoblasts, reducing Ca²⁺ deposition in bone. In the kidneys and intestines, PTH stimulates the reabsorption of Ca²⁺. While PTH acts directly on the kidneys to increase Ca²⁺ reabsorption, its effects on the intestine are indirect. PTH triggers the formation of calcitriol, an active form of vitamin D, which acts on the intestines to increase absorption of dietary calcium. PTH release is inhibited by rising blood calcium levels.

The hormone calcitonin is produced by the parafollicular or C cells of the thyroid and has the opposite effect on blood calcium levels as PTH. Calcitonin decreases blood calcium levels by inhibiting osteoclasts, stimulating osteoblasts, and stimulating calcium excretion by the kidneys. This results in calcium being added to the bones to promote structural integrity. Calcitonin appears to play a major plasma calcium homeostasis role only in children, and in pregnant women to reduce maternal bone loss. Its role in adults is not well understood and it may be more important in regulating bone remodeling than blood plasma homeostasis.

Hormonal regulation is required for the growth and replication of most cells in the body. Growth hormone (GH) produced by the anterior pituitary accelerates the rate of protein synthesis, particularly in skeletal muscle and bones. Growth hormone has direct and indirect mechanisms of action. One direct action is the stimulation of fat breakdown (lipolysis) and release into the blood by adipocytes. This results in a switch by most tissues from utilizing glucose as an energy source to utilizing fatty acids. This process is called a glucose-sparing effect. Another direct action occurs in the liver, where GH stimulates glycogen breakdown, and subsequent release of glucose into the blood. Blood glucose levels increase as most tissues are metabolizing fatty acids instead of glucose. The GH-mediated increase in blood glucose levels is called a diabetogenic effect because it is similar to the high blood glucose levels seen in diabetes mellitus.

The indirect mechanism of GH action is mediated by somatomedins or insulin-like growth factors (IGFs), which are a family of growth-promoting proteins produced by the liver. IGFs stimulate the uptake of amino acids from the blood, allowing the formation of new proteins, particularly in skeletal muscle cells, cartilage cells, and other target cells. GH levels are regulated by two hormones produced by the hypothalamus. GH release is stimulated by growth hormone-releasing hormone (GHRH) and is inhibited by growth hormone-inhibiting hormone (GHIH), also called somatostatin. Both of these are produced by the hypothalamus and delivered to the anterior pituitary by the hypophyseal portal vein.

Over-secretion of growth hormone can lead to gigantism in children, causing excessive growth. In adults, excessive GH can lead to acromegaly, a condition in which bones still capable of growth in the face, hands, and feet enlarge. Under-production of GH in adults does not appear to cause any abnormalities, but in children it can result in pituitary dwarfism, in which growth is proportionally reduced.

When a threat or danger is perceived, the body responds by releasing hormones that will ready it for the fight-or-flight response. The effects of this response are familiar to anyone who has been in a stressful situation: increased heart rate, dry mouth, butterflies in your stomach and sweating. This is what we call a short-term stress. When one is under stress for more than several hours (or chronically), it translates into long term stress.

The sympathetic nervous system regulates the stress response via the hypothalamus. Stressful stimuli cause the hypothalamus to signal the adrenal medulla via nerve impulses, which mediates short-term stress responses, and to the adrenal cortex, via the hormone adrenocorticotropic hormone (ACTH), which mediates long-term stress response.

The digestive system is basically a tube within our body, from mouth to anus. It includes the stomach and intestines, as well as accessory organs such as the liver, gall bladder and pancreas. The space within any tubular body structure, such as blood vessels or this digestive tract, is known as a lumen. During embryological development, embryonic cells (endoderm) forming the primitive yolk sac, turn outside-in (invaginates) forming the anal opening to the outside. This endoderm layer becomes the epithelial tissue lining of the future gastrointestinal (GI) tract and many associated organs. Later in the development process, the mouth opening breaks through the outer layer of embryonic cells (ectoderm) from the opposite side, meeting the endoderm. This ectoderm lines the mouth and forms the salivary glands. As a result, anything inside the space or lumen of the GI tract can technically be described as still being “external” to the body tissues. So, the caustic process of digestion is occurring in an “external” tube, without destroying the “internal” body tissues themselves. Then the products of digestion are absorbed from this “external environment” into the body cells and tissue fluids.

As early as the 2nd century, early anatomists understood the basic structure and important function of the digestive system. Many of the terms we still use for anatomy were developed then and during the medieval period, when they described the importance of the stomach and intestines for proper nutrition and digestion to maintain health. They also recognized the association of the liver and gall bladder to produce and store bile, although they didn’t correctly understand its physiology. It was identified as one of the four body fluids (blood, phlegm, yellow bile and black bile) that Hippocrates proposed were the physiological foundation for different human emotions and behaviors; thus they were called “humors”. The imbalance of these four humors was thought to be the cause of physical and mental illnesses. This and many of the early physiological theories have since been discarded. However, their idea that the stomach was an animate organ with ability to think or feel doesn’t seem totally ridiculous as you learn about how modern science is discovering the physiological importance of a specific part of the nervous system that resides entirely in our gut. By the renaissance period, physiologists were focusing their research on the chemical basis of digestion occurring inside the GI tract.

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Several of the core ideas in A&P are clearly demonstrated as you investigate the digestive system in this module:

1. Living organisms are causal mechanisms whose functions are to be understood by the applications of the laws of physics and chemistry.

   Both mechanical and chemical digestion are necessary to convert the food we eat into a form that can be absorbed.

2. The cell is the basic unit of life and cell plasma membranes control transport and signaling necessary for life.

   Specialized cells are able to secrete substances into the digestive system space (lumen), to protect the body from this mixture because some of these substances would otherwise digest the body, and then to absorb specific substances from the mixture into the body.

3. Life requires information flow within and between cells and between the environment and the organism.

   Receptors monitor the composition of the mixture as it moves through the digestive system lumen, stimulating secretion of hormones and nerve impulses that coordinate the release of substances and control the movement from one segment to another by circular muscles called sphincters.

4. Living organisms must obtain matter and energy from the external world. This matter and energy must be transformed and transferred in varied ways to build the organism and to perform work.

   Food in the diet must be broken down into its basic units for absorption and then these are used to fuel ATP production, build and repair cells and tissues, and participate in other metabolic activities of the body.

5. Homeostasis (and “stability” in a more general sense) maintains the internal environment in a more or less constant state compatible with life.

   In addition to nutrients, the absorption of vitamins, electrolytes and water are critical to maintaining body homeostasis, with disorders and diseases occurring when malabsorption occurs.

6. Understanding the behavior of the organism requires understanding the relationship between structure and function (at each and every level of organization).

   This is best illustrated by the concept of increased surface area for efficient absorption in the digestive system.

7. Living organisms carry out functions at many different levels of organization simultaneously.

   Cell level function is supported by all the tissue structures that make up the different segments and organs of the digestive system.

8. All life depends upon the proper interactions and supporting functions among interrelated organ systems.

   In addition to obtaining necessary metabolic substances needed by all other body systems, the digestive system has several mechanisms to protect other systems against pathogens that can enter with things we ingest.

Here is a preview of each of the modules to come:

• Structures and Functions, will explore how the major organs of the digestive system are able to accomplish the major system level functions:
  • movement through the length of the digestive system
  • complementary mechanisms for digestion in different segments
  • structural components enhancing efficient absorption

  Pay attention to not only what structures are similar and what are unique in the different sections, but how this contributes to the overall function of the system as a whole.

• Levels of Organization, will examine this structure and function in more detail, progressing through the major levels of organization in the human organism from the chemical and cellular levels to the tissues, organs and organ systems:
  • nutritive and digestive molecules
  • cells of the stomach, small and large intestine, liver, and pancreas
  • tissue layers and organs that make up the GI tract, from mouth to anus
  • accessory organs that contribute secretions to the GI tract

  Pay attention to the function of cells for both secretion and absorption of specific substances in the different parts of the digestive tract and accessory organs. What these specific cells produce and how they move materials across cell membranes is critical to understanding the function of the system as a whole.

• Homeostasis, will delve into how this system contributes to the body’s natural tendency to maintain a stable internal environment:
  • how hormones and nerves control and coordinate the digestive system
  • what happens when digestive system malfunctions

  Pay attention to how not only is the rate of movement from one section to another controlled, but what is released into the lumen is controlled based on monitoring of content of food eaten. Don’t get the endocrine secretion of hormones into the blood for control and regulation confused with the exocrine secretion of substances into the lumen for the digestion and absorption processes – both are happening.

• Integration of Systems, will investigate which systems are subsets of larger systems, and how they function together in harmony and conflict:
  • how digestive system interacts with the other body systems
  • how other systems affect the digestive system functions

  Pay attention to the relationship between proper movement and secretion for digestion and the subsequent absorption and transport of materials for metabolism. This links the digestive tract and accessory digestive organs to the other systems.

The digestive system moves water, nutrients and electrolytes from the external environment to the internal environment. Within the digestive system, the gastrointestinal tract is a continuous hollow tube from the mouth to the anus and is technically contiguous with the external environment. This internal space is called a lumen. All digestive system organs play vital roles in breaking down food moving through the gastrointestinal tract into its chemical building blocks, absorbing these building blocks into the blood, and eliminating residual indigestible materials.

Different parts of the digestive system will secrete substances into the digestive tract lumen. These secretions come from both the cells that make up the epithelial lining of the digestive tract and from exocrine accessory organs that have ducts emptying into the tube. These substances will assist with the movement of food from one part of the tract to the next (such as mucus) and with the digestion of the food while it is in the tube (such as enzymes).

In order to absorb digested substances, that material has to be first moved from the lumen, into the apical or tube-side of the epithelial cells lining the digestive tract, then out of the other basal side of those cells, into the body’s interstitial fluid, and into blood or lymph capillaries for transport through the body. This process can happen passively or require ATP cellular energy. You may want to review membrane transport in the cell module. Various chemicals secreted into the lumen can enhance the absorption of some material, such as vitamins and lipids. Anatomical structures that increase the area of the absorptive surface exposed to the digested substances in the tube will also enhance absorption.

There will be another kind of secretion involved in regulating this whole process, including how long food stays in one section of the digestive tract for the most efficient digestion or absorption. These are endocrine secretions from cells that are part of the digestive organs themselves. These hormones are secreted into the blood, not the digestive lumen, and transported by blood to target cells of the digestive system organs. In this way, it helps regulate and coordinate the functions among the different organs. The autonomic nervous system also plays a role in regulating and coordinating the digestive system.

We usually don't think about the digestive system until something goes wrong with it – when we get indigestion, nausea, or diarrhea. We seldom appreciate that the digestive system is a complex string of organs that make up the body's engine, turning fuel from the food we eat into energy that keeps us going. Each organ of the digestive system performs specific functions but all these organs work together to digest the foods we eat and absorb the nutrients into our bodies. Feel free to review the overall Digestive system in the course Introduction.

The digestive system is generally divided into two main categories: organs of the alimentary canal (aliment = “nourish”) and accessory digestive organs. The alimentary canal, also called the gastrointestinal (GI) tract or gut, is a continuous muscular tube that runs from the mouth to the anus. The internal space of this tube is called the lumen. The GI tract is involved with the digestion of food –its breakdown into smaller fragments – and the absorption of digested food fragments from the lument through the alimentary canal wall and into the bloodstream. The accessory digestive organs contribute to secretions to the GI tract, but the food doesn't pass through these organs.

Digestive System organs. This work by Cenveo is licensed under a Creative Commons Attribution 3.0 United States (http://creativecommons.org/licenses/by/3.0/us/).

Different digestive system organs are responsible for different digestive processes and functions. These functions include: extracting nutrients from food and removing waste. The processes by which these occur are called ingestion, motility of food through the GI tract lumen, mehcanical and chemical digestion of the food, absorption and breakdown of products, defecation to remove residues.

Both voluntary skeletal muscles and involuntary smooth muscles are involved in propelling food material through the digestive system. Skeletal muscles of the tongue are involved in the voluntary first phase of swallowing, but then it becomes an involuntary reflex with skeletal muscles of the pharynx. You will learn more about this swallowing process called deglution in the next module.

The smooth muscle of the GI tract is arranged in two layers: longitudinal along the length of the tube and circular around the diameter of the tube. Coordinated contraction and relaxation of these two layers creates a wave-like propulsion of the food called peristalsis. Muscles in the esophagus mechanically transport the food via peristalsis from the mouth to the stomach. An extra smooth muscle layer in the stomach adds a churning movement within the stomach. Peristalsis continues to propel food through the small and large intestines.

Controlling the rate of food moving from one organ of the digestive tract to the next are specialized circularly arranged skeletal and smooth muscles called sphincters. Sphincters are typically contracted and relax only to allow food to move from one organ to the next. The majority of sphincters along the length of the GI tract are involuntary smooth muscle structures. The esophageal sphincter helps separate the esophagus from the stomach to maintain linear movement and protect the esophagus from acidic chemicals of the stomach. The pyloric sphincter separates the stomach from the small intestine; again there is a physical separation for compartmentalization and to maintain directionalized movement.

Material then snakes its way through the small intestine and the iloeocecal sphincter controls movement into the large intestine or colon. The anal sphincter muscle is skeletal muscle controlled consciously to relax during defecation. There is also a hepatopancreatic sphincter that controls the release of accessory secretions from the liver and pancreas into the beginning of the small intestine.

Digestion is accomplished both mechanically and chemically. Mechanical digestion physically breaks food into smaller pieces, increasing surface area for more efficient chemical digestion. Chemical digestion breaks large food macromolecules down into their chemical building blocks, which can then be absorbed through the intestinal wall and into the general circulation.

Food is ingested in the mouth where it begins mechanical digestion from the grinding of the teeth and chemical digestion from enzymes in the saliva. Chemical digestion starts in the saliva and follows into the stomach. In the stomach material is broken down into smaller components by chemically strong acids, enzymes and mechanical churning. However, the small intestine is the site of most chemical digestion, and almost all absorption. Enzymes, bile, bicarbonate and other materials are mixed in from the pancreas and liver to promote chemical digestion and allow enhanced adsorption. Enzymes are responsible for the majority of this chemical digestion. The breakdown of fat also requires emulsification by bile, secreted by the liver and stored in the gall bladder.

The mechanical and chemical digestive processes that begin in the mouth and continue through the small intestine have one endpoint: to convert food into substances that can be absorbed from the lumen by epithelial cells in the lining of the GI tract and then enter blood or lymphatic vessels. Absorbable substances are the monosaccharides, glucose, galactose, and fructose from carbohydrates; single amino acids, dipeptides, and tripeptides from proteins; and monoglycerides, glycerol, and fatty acids from lipids such as triglycerides.

Most nutrients are absorbed into digestive epithelial cells by active transport mechanisms. Nutrients not absorbed through active transport include lipids, lipid-soluble vitamins, and most water-soluble vitamins. With the help of bile salts, the breakdown products of lipids are transported into intestinal cells in structures called micelles. These absorbed fats then aggregate into chylomicrons for transport.

These substances absorbed into the epithelial cells of the digestive tract are then absorbed into either the circulatory or lymphatic capillaries for transport where needed by body cells for metabolism. Absorption from the GI lumen is enhanced by increasing the surface area. Most absorption occurs in the small intestine, the longest organ of the GI tract. Several anatomical structures at the organ, tissue, and cell level also improve nutrient, water and electrolyte absorption.

Surface Area

In order to get the various materials needed for energy production and anabolic metabolism in all body cells, our body has to exchange nutrients, water and electrolytes from the environment. However, the substance taken into the space of the GI tract is not always in the form that can be absorbed, so it must first be broken down. Various secreted chemicals are critical to accomplishing this digestion. These ingested macromolecules are digested in different regions of the GI tract, requiring that the mixture of material be moved through the digestive system in a controlled way. Once it has been digested to a basic chemical structure, the material can be absorbed into the blood or lymph. At that point, the other body systems integrate to distribute these absorbed nutrients, fluids and electrolytes through the body as needed. Any material remaining in the GI tract as waste will then be removed from the body by defecation.

To understand these system-level functions, you will be further exploring structures and processes occurring at all levels of organization. Some examples of major digestive structures assigned to their structural level of organization of the digestive system include:

1. Chemical level - sodium, potassium, chloride, bicarbonate, and phosphate ions and hydrochloric acid
2. Macromolecular level - enzymes of digestion, bile, and the nutritive molecules such as carbohydrates, protein, lipids and nucleic acids
3. Cellular level – mucosa cells, secretory cells, and immune cells
4. Tissue level – epithelial, connective, and smooth muscle tissues
5. Organ level - gastrointestinal tract and accessory organs
6. Organ System level - integration of organs for nutrient and waste movement, digestion and absorption

The digestive system breaks down ingested material into absorbable components (nutrients) that the rest of the body can use to maintain adequate function. We require a diverse set of nutrients to support energy production, carry out metabolism and maintain structure.

Chemical digestion generally, breaks down large food molecules into their respective chemical building blocks, called monomers, that can be absorbed. The enzymes responsible for chemical digestion are released by both intrinsic glands found in the gastrointestinal tract and the accessory glands which secrete molecules into the gastrointestinal tract.

Hydrolysis refers to the breakdown of a chemical where water breaks a covalent bond. Hydrolysis can happen spontaneously, but the breakdown of food into macromolecules and monomers occurs by enzymatic hydrolysis - where the hydrolysis reaction catalyzed by an enzyme. Hydro- is part of the name because a water molecule is added to each molecular bond that is broken, or -lysed. More specifically, hydrolysis is a method of degradation which splits a molecule of water to help break chemical bonds in a larger molecule. Usually an H+ is attached to one of the components and an OH- group to the other. Hydrolysis reactions are important for many other physiologic processes in the body in addition to the breakdown of food molecules.

Hydrolysis of a Sucrose molecule into Glucose and Fructose.

For a review of nutritive molecules, including chemical structure and bonds, revisit the Chemical Bonding and Molecules page and the rest of the Levels of Organization unit.

The nutritive organic compounds in our food includes carbohydrates, proteins and lipids. These molecules are digested, then absorbed, and reassembled into macromolecules or used as fuel for metabolism in the body. The process of breaking down these macromolecules involves splitting into smaller molecules using water molecule, thus the name hydrolysis (“hydro” = water; “lysis” = splitting). The reverse reaction, called dehydration synthesis, can build macromolecules from the absorbed building blocks. Enzymes can speed up the rate of these reactions.

Carbohydrates

Our daily food intake usually includes from 200 to 600 grams of carbohydrates. Carbohydrates are primarily used for quick energy, but some are also used to create important signaling and structural molecules. The monomers of carbohydrates, monosaccharides (simple sugars), are absorbed easily and can therefore be a source of quick energy for the body when we consume them in this form. Glucose, galactose, and frutose are the three common monosaccharides in our diet.

Hydrolysis: carbohydrate digestion

Disaccharides are two monosaccharides bound together and include sucrose (table sugar), lactose, and maltose. Polysaccharides are long chains of monomers and include polymerized glucose in different forms including glycogen, which is the stored form of glucose in our bodies, and starch, a polysaccharide of glucose molecules that comes from plant sources.

In many places around the world, starch accounts for the largest portion of digestible carbohydrates in the diet, with the addition of some glycogen, disaccharides and monosaccharides. There are other polysaccharides in our diet, like cellulose, but our bodies do not produce enzymes that can break them down, so they are indigestible. While indigestible polysaccharides do not give us any nutrients, they do provide bulk (fiber) that helps propel food through the digestive system.

Proteins

We get protein when we eat meat, seafood, eggs, beans, nuts and soy products. USDA recommends 5 to 6 ounces of protein in diet per day, although children need less. This dietary protein is usually in the form of polypeptides and must be digested into its amino acid building blocks for absorption. There are numerous enzymes that break large proteins into smaller peptides and then into amino acids. Amino acids are then absorbed from the digestive system into the circulatory system where they are delivered throughout the body. Once amino acids have entered cells throughout the body, they are bonded together to make proteins needed for cell function. As a last resort, proteins and amino acids can also be used as energy; they are metabolically converted to glucose before they are used as energy sources.

Hydrolysis: protein digestion

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Lipids and Fats

Dietary lipids include fats and oils. While not considered a USDA food group, oils contain some essential nutrients and are recommended as part of a healthy diet, although only in small amounts. Solid fats have more saturated and trans-fatty acids and are considered empty calories when included in a diet because they add calories but not needed nutrients. Most dietary lipids are in the form of triglycerides, with one glycerol molecule and three fatty acids bound together. Lipids are processed by enzymes secreted from the pancreas (with some enzymes from the stomach and saliva) and are then solubilized for absorption by salts secreted in bile (from the liver). These steps prepare them for absorption in the small intestine. Like proteins, ingested lipids are broken down into smaller parts for absorption and then are either metabolized to make energy or are use to make cellular structures including cell membranes. Lipid absorption is also required for absorption of some fat-soluble vitamins.

Hydrolysis: lipid digestion

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Some salivary glands are always secreting saliva. Intrinsic salivary glands of the mouth secrete small amounts of saliva, usually just enough to moisten the mucous membranes and clean the mouth and teeth. The accessory salivary glands are exocrine organs under autonomic nervous system control with ducts leading into the mouth. Secretion increases when there is food in the mouth, as well as through a reflex when food is smelled, seen or thought about (you have probably heard about Pavlov’s experiment with the salivating dog and bell). Saliva is needed to moisten and lubricate the food and begin its chemical breakdown.

Saliva is mainly water, which dissolves chemicals in the food. Only dissolved chemicals can activate the different kinds of taste receptor cells on the tongue, palate and other parts of the mouth and pharynx. Mixed in with the water, saliva also contains mucus, various electrolytes typically found in blood plasma, as well as some digestive molecules, metabolic waste products and immune molecules. Each of these contributes to the various functions of saliva.

Bicarbonate and phosphate ions help maintain the pH of saliva as neutral or slightly basic (average 7.4 pH). This not only helps protect the teeth from acidic substances eaten and plaque bacteria that grow best in an acidic environment, but also maintains the optimal pH for the enzyme amylase. Salivary amylase starts breaking complex carbohydrates eaten, like starch, into sugars. This enzymatic activity will stop once the mixture of food and saliva, called a bolus, is swallowed and reaches the acidic environment of the stomach. Salivary lipase is another enzyme in saliva that breaks down dietary lipids, but it is activated when it reaches the acidic gastric juice with its optimal pH being much more acidic than the salivary pH.

In addition to the water of saliva, mucus in the saliva is composed of glycoproteins and helps moisten the food, so it can be manipulated into a mass for swallowing. It also helps lubricate the movement of food through the pharynx and esophagus by peristalsis. Lysozyme antimicrobial enzymes and antibodies (Immunoglobulin A) in the saliva help combat pathogens that might enter the body with food or drink. Like the sweat glands, salivary glands play a role in some metabolic waste excretion, so urea and ammonia are also found in saliva.

Production of Hydrochloric Acid (HCl). This work by Cenveo is licensed under a Creative Commons Attribution 3.0 United States (http://creativecommons.org/licenses/by/3.0/us/).

The bicarbonate ion (HCO₃^-) is then exchanged for a chloride ion (Cl^-) on the basal side (away from the lumen) of the cell. Potassium (K⁺) and chloride (Cl^-) ions diffuse into the secretory region of the cell called the canaliculi. Then the potassium is exchanged in this region for hydrogen ions via a H+/K+ ATPase. The hydrogen ions, which are millions of times more concentrated in this region of the cell than any other, are then pumped from the canaliculi into the lumen of the stomach. The following video illustrates this process.

Production of Hydrochloric Acid in the Stomach

A single layer of epithelial cells forms the inner most later of the stomach, called the mucosa. The mucosa is marked by depressions called gastric pits (these are lined with epithelial cells). The gastric gland is at the bottom of the pit, which contain multiple cell types: mucous cells, stem cells, parietal cells, chief cells, and G cells (enteroendocrine cells).

Cells of the gastric pit in the mucosa. This work by Cenveo is licensed under a Creative Commons Attribution 3.0 United States (http://creativecommons.org/licenses/by/3.0/us/).

The pancreas is responsible for both endocrine (hormone secretion) and exocrine (enzyme secretion) function. Cells are organized into clusters throughout the pancreas.

Pancreas cellular structures, particularly beta cells that produce insulin. This work by Cenveo is licensed under a Creative Commons Attribution 3.0 United States (http://creativecommons.org/licenses/by/3.0/us/).

Throughout the gastrointestinal (GI) tract, walls are comprised of the same four fundamental tissue layers. From the lumen of the GI tract, these layers are the mucosa, submucosa, muscularis, and serosa.

The lining of the small intestine. Image courtesy of Dr. Allan Wiechmann, University of Oklahoma Health Sciences Center

Tissue layers of the GI tract. This work by Cenveo is licensed under a Creative Commons Attribution 3.0 United States (http://creativecommons.org/licenses/by/3.0/us/).

The peritoneum, is the largest serous membrane in the body and lines the abdominal cavity. The tissue has several components including the the mesothelium and an underlying supporting areolar connective tissue layer. The connective tissue in turn has two layers: the parietal peritoneum, which lines the abdominal wall, and the visceral peritoneum, which covers some organs and serves as their serosae. The peritoneal cavity is the small space between the parietal and visceral peritoneum that contains the lubricating serous fluid.

The peritoneum includes large folds that bind organs to each other and to the abdominal walls. This keeps the organs in the proper place and suspends them when we are upright. Within these folds are blood vessels, lymphatic vessels, and nerves that innervate the abdominal organs.

The cheeks, tongue, hard palate, and soft palate frame the mouth, also called the oral cavity or buccal cavity. The mouth is involved in both mechanical and chemical digestion. Mechanical digestion consists of mastication (chewing), in which the tongue manipulates food, the teeth grind it, and saliva mixes with it. Mastication turns food into an easy-to-swallow bolus and breaks the food into smaller pieces so that there is more contact area for digestive enzymes.

The cheeks make up the oral cavity's lateral walls. The outer covering of the cheeks is the skin, and the inner covering is the mucous membrane. This membrane is made up of nonkeratinized stratified squamous epithelium; the multiple layers are resistant to abrasion. Between the skin and mucous membranes are connective tissue, fat tissue and buccinator muscles.

The bounds of the oral cavity. This work by Cenveo is licensed under a Creative Commons Attribution 3.0 United States (http://creativecommons.org/licenses/by/3.0/us/).

The lips, also called labia ("fleshy borders"), encircle the opening of the mouth. Their outer covering is skin, and their inner lining is mucous membrane. Between these two layers is the orbicularis oris muscle. The labial frenulum is a midline fold of mucous membrane that attaches the inner surface of each lip to the gum. When we chew food, the buccinator muscles in the cheeks and the orbicularis oris muscle in the lips contract, which keeps food between the lower and upper teeth. These muscles also play a role in speech.

The area between the lips (or cheeks) and teeth is called the oral vestibule. The oral cavity is the area than runs between the gums and teeth and the entrance to the throat (oropharynx), also called the fauces ("passages"). If you puff out your cheeks, you can increase the size of the oral vestibule but not the oral cavity.

The septum that separates the oral cavity and nasal cavity is called the palate. Anatomically, a septum (plural, septa) is a wall within a single organ or cavity that separates the space into distinct sides. For example, the nasal septum divides the nostrils. This is separating two distinct cavities.

Structures of the oral cavity. This work by Cenveo is licensed under a Creative Commons Attribution 3.0 United States (http://creativecommons.org/licenses/by/3.0/us/).

The palate, which forms the roof of the mouth, is what allows us to breathe while chewing food. The anterior part of the roof of the mouth is called the hard palate. It is created by the maxillae and palatine bones and is covered by mucous membrane. The hard palate makes up the bony wall between the oral and nasal cavities. The posterior part of the roof of the mouth, the soft palate, is also lined with mucous membrane. This arch-shaped muscular structure forms a dividing wall between the oropharynx and nasopharynx.

The uvula (Latin for ‘little grape’) is a cone-shaped muscular process that hangs from the end of the soft palate. It plays a role in speech and articulation of words. It also plays a small role in preventing foods and liquids from entering the nasal cavity. Two muscular folds on each side of the base of the uvula extend down the lateral sides of the soft palate. The anterior fold is called the palatoglossal arch, which terminates next to the base of the tongue. The posterior fold, the palatopharyngeal arch, lies at the interface with the pharynx. Between these two arches on the lateral wall are the palatine tonsils. The lingual tonsils are located at the base of the tongue.

There are also many small, intrinsic salivary glands within the mucous membrane of the mouth and tongue. Their secretion is independent of the presence of food. These glands either open directly into the oral cavity or indirectly through short ducts. Small amounts of saliva are secreted by the labial glands in the lips, the buccal glands in the cheeks, the palatal glands in the palate, and the lingual glands in the tongue.

The tongue is composed of skeletal muscle covered with a surface of nonkeratinized stratified squamous epithelium and a mucous membrane covering. The tongue and its associated muscles make up the floor of the oral cavity. A median septum extends the entire length of the tongue, dividing it into symmetrical halves. Inferiorly, the tongue is attached to the mandible, styloid process of the temporal bone, and hyoid bone.

The tongue. This work by Cenveo is licensed under a Creative Commons Attribution 3.0 United States (http://creativecommons.org/licenses/by/3.0/us/).

Each half of the tongue has the same number and type of intrinsic and extrinsic muscles. As you learned in your studies of the muscular system, extrinsic muscles of the tongue are the hyoglossus, genioglossus, styloglossus and palatoglossus muscles. These muscles originate outside the tongue and insert into connective tissues within the tongue. They move the tongue from side to side and in and out, performing three important digestive functions: (1) moving food for optimal chewing, (2) shaping food into a bolus (rounded mass), (3) pushing food toward the back of the mouth to be swallowed and (4) elevates the posterior part of the tongue to assist in swallowing. Conscious control of the tongue also aids in speaking and other non-digestive processes.

The intrinsic muscles are the longitudinalis superior, longitudinalis inferior, transversus linguae, and verticalis linguae muscles (lingua and lingual refers to the tongue). These muscles both originate in and insert into connective tissues within the tongue. They change the size and shape of the tongue to facilitate swallowing and speech. A fold of mucous membrane in the middle inferior region (underside) of the tongue, the lingual frenulum, attaches to the floor of the mouth and limits the tongue's posterior movement. People with a condition called ankyloglossia have a too short or too rigid lingual frenulum, which impairs their speech. As a result, they are sometimes referred to as "tongue-tied."

The top and sides of the tongue are studded with papillae ("nipple-shaped") extensions of lamina propria layer of mucosa, which are enshrouded in stratified squamous epithelium. Most of these papillae contain taste buds; those without taste buds have touch receptors to give a sense of food’s texture. The latter increase the amount of friction between the tongue and food, which helps the tongue move food around in the mouth. Lingual glands, are found on the anterior, inferior surface of the tongue, in the lamina propria of the tongue secrete mucus and a watery serous fluid that contains the enzyme lingual lipase, which begins the digestion of triglycerides.

Specific teeth and structures of the mouth. This work by Cenveo is licensed under a Creative Commons Attribution 3.0 United States (http://creativecommons.org/licenses/by/3.0/us/).

The teeth, or dentes, are secured in sockets of the alveolar processes of the maxillae and mandible. Gingivae (gums; singular gingiva) cover the alveolar processes. Lining the sockets is the periodontal ligament, a dense fibrous connective tissue that secures the teeth in place. The teeth are covered by enamel, which is the hardest substance in the body. Enamel helps prevent teeth from being worn down when we chew, and it helps keep out acids that could easily dissolve the interior of a tooth.

Humans have two sets of teeth (dentitions). The 20 deciduous teeth, or baby teeth, first appear at about 6 months of age. Between ages 6 and 12 years, these teeth are replaced by the 32 permanent teeth. Closest to the midline are the two incisors, chisel-shaped teeth we use for cutting into food. The cuspids (canines) are next to the incisors. A cuspid’s pointed edge (cusp) tears and shreds food. Posteriorly, the next teeth are the two premolars (bicuspids) followed by up to three molars. Premolars and molars have broader, flatter surfaces, which we use to crush and grind food.

The pharynx (throat) is a funnel-shaped tube that runs from the choanae (internal nostrils) to the esophagus posteriorly and to the larynx anteriorly. The pharynx has three subdivisions: the nasopharynx, the oropharynx, and the laryngopharynx. The nasopharynx acts as a passageway for air during ventilation, while the other two subdivisions participate in both ventilation and digestion. Superiorly, the oropharynx is connected with the nasopharynx, inferiorly with the larynx and laryngopharynx, and anteriorly with the mouth.

The Pharynx. This work by Cenveo is licensed under a Creative Commons Attribution 3.0 United States (http://creativecommons.org/licenses/by/3.0/us/).

Histologically, the wall of the pharynx is similar to that of the oral cavity. The mucosa includes a epithelium with mucous-producing glands. The nasopharynx is lined with pseudostratified columnar epithelium; the oropharynx and laryngopharynx are lined with stratified squamous. There are two skeletal muscle layers in the external muscle layer of the pharyngeal wall. Cells in the inner layer extend longitudinally. In the outer layer, the superior, middle, and inferior pharyngeal constrictor muscles are stacked, one inside the other, like flowerpots. Contraction of these muscles propels food toward the esophagus.

When swallowed food enters the oropharynx and laryngopharynx, it provokes contractions of the pharyngeal constrictor muscles that help push food into the esophagus. Usually during swallowing, the soft palate moves back to close off the nasopharynx, while the trachea ("windpipe") moves up under the epiglottis to cover the glottis (the opening to the larynx or voice box); this effectively blocks off air passages. But we all know what it feels like to have food "go down the wrong tube," which means it either goes into the nasal cavities or the trachea. When food enters the trachea, our reaction is to cough, which usually forces the food up and out of the trachea and back into the pharynx.

The Esophagus. This work by Cenveo is licensed under a Creative Commons Attribution 3.0 United States (http://creativecommons.org/licenses/by/3.0/us/).

The esophagus is a collapsible tube located posterior to the trachea. This muscular tube is about 10 inches long. The esophagus runs a mainly straight route through the mediastinum of the thorax. To enter the abdomen, the esophagus penetrates the diaphragm through an opening called the esophageal hiatus. At the cardiac orifice, the esophagus joins with the stomach. Surrounding this orifice is the lower esophageal sphincter (also called the gastroesophageal or cardiac sphincter). Remember that sphincters are circular muscles that surround tubes and serve as valves, closing the tube when the sphincters contract and opening it when they relax. The lower esophageal sphincter relaxes to let food pass into the stomach, then contracts to prevent stomach contents from backing up into the esophagus. Surrounding this sphincter is the muscular diaphragm, which helps close off the sphincter when no food is being swallowed. When the lower esophageal sphincter does not completely close, some of the stomach contents can reflux (i.e., back up into the esophagus), causing heartburn or gastroesophageal reflux disease (GERD).

The esophageal mucosa is made up of nonkeratinized stratified squamous epithelium, lamina propria, and a muscularis mucosa. The mucosa near the stomach also includes mucous glands. The stratified squamous epithelium protects against abrasion and erosion from food particles. In the superior third of the esophagus, the muscularis is skeletal muscle, in the middle third it is both skeletal and smooth muscle, and in the inferior third it is smooth muscle. A slight prominence at either end of the esophagus creates two sphincters: the upper esophageal sphincter, made of skeletal muscle, and the lower esophageal sphincter, made of smooth muscle. As we have already learned, the superficial layer of the esophagus is called the adventitia, not the serosa. In contrast to the stomach and intestines, the areolar connective tissue of the adventitia is not covered by mesothelium.

The esophagus secretes mucus that lubricates food, and it propels food into the stomach. Chemical digestion that began in the mouth continues in the esophagus, but there aren’t any new digestive enzymes secreted. The upper esophageal sphincter controls the movement of food from the pharynx into the esophagus. The lower esophageal sphincter controls the movement of food from the esophagus into the stomach. Rhythmic waves of peristalsis begin in the esophagus and then continue in the rest of the digestive tract organs. The feeling of having a lump in your throat when you are nervous is caused by peristalsis that occurs when there is no food in the esophagus.

Deglutition is another word for swallowing – the movement of food from the mouth and into the stomach. The entire process takes about four to eight seconds for solid or semisolid food and about one second for very soft food and liquids. Deglutition involves the mouth, pharynx, and esophagus. It is facilitated by the secretion of mucus and saliva. There are three stages in deglutition: the voluntary phase, the pharyngeal phase, and the esophageal phase.

Bolus position during deglutition. This work by Cenveo is licensed under a Creative Commons Attribution 3.0 United States (http://creativecommons.org/licenses/by/3.0/us/).

The voluntary phase of deglutition is also called the oral phase or buccal phase. In this phase, swallowing is set in motion when the tongue moves upward and backward against the palate, pushing the bolus to the back of the oral cavity and into the oropharynx. At this point, the two involuntary phases of swallowing begin.

In the pharyngeal phase, stimulation of receptors in the oropharynx sends impulses to the deglutition center (a collection of neurons that controls swallowing) in the medulla oblongata. Impulses are then sent back to the uvula and soft palate, provoking them to move upward to close off the nasopharynx. Sequential contractions of the pharyngeal constrictor muscles move the bolus through the oropharynx and laryngopharynx. Relaxation of the upper esophageal sphincter then allows food to enter the esophagus.

The entry of food into the esophagus marks the beginning of the esophageal phase of deglutition. Peristalsis propels the bolus through the esophagus and toward the stomach. The circular muscle layer of the muscularis immediately superior to the bolus contracts, pinching the esophageal wall, forcing the bolus forward. At the same time, the longitudinal muscle layer of the muscularis inferior to the bolus also contracts, shortening this inferior area and pushing out its walls to receive the bolus. Waves of contractions keep moving the food toward the stomach. When the bolus nears the stomach, relaxation of the lower esophageal sphincter allows the bolus to pass into the stomach. During the esophageal phase, esophageal glands secrete mucus that lubricates the bolus and minimizes friction. Peristalsis is completely involuntary even though there is skeletal muscle in the first 2/3 of the esophagus.

The stomach is an expansion of the GI tract that lies below the esophagus. It is a very mobile structure between its relatively fixed upper and lower ends. The stomach is found between the esophagus to the first part of the small intestine (the duodenum). The stomach's position and size are always changing. It is about as big as a large sausage when empty, and stretches to hold 1 liter of food when full; the stomach has a final capacity of 2-3 liters. One of the digestive functions of the stomach is to serve as a temporary "holding chamber". This is an important step in digestion, because we can eat a meal far more quickly than it can be digested and absorbed in the small intestine. So the stomach pushes only a small amount of food into the small intestine at a time.

The stomach plays several important roles in chemical digestion, including the continued digestion of starch and the initial digestion of proteins and triglycerides. The stomach is also where the semisolid bolus is converted to a liquid (chyme) and where some ingested substances are absorbed.

Stomach Anatomy

There are four main regions in the stomach: the cardiac, fundus, body, and pylorus. The cardiac (cardia region) is a small area surrounding the cardiac orifice through which food from the esophagus enters the stomach. Lying beneath the diaphragm, superior and to the left of the cardiac, is the dome-shaped fundus, which functions as a temporary storage center for food. Inferior to the fundus is the body, the large central part of the stomach. The funnel-shaped pylorus connects the stomach to the duodenum. The pyloric antrum is the wider, more superior portion of the pylorus that connects to the body of the stomach. The pyloric antrum narrows into a region called the pyloric canal, which leads into the duodenum. The pylorus communicates with the duodenum via the smooth muscle pyloric sphincter. This sphincter controls stomach emptying. In the absence of food, the stomach deflates inward and its mucosa and submucosa fall into large folds called rugae.

Stomach anatomy. This work by Cenveo is licensed under a Creative Commons Attribution 3.0 United States (http://creativecommons.org/licenses/by/3.0/us/).

The convex lateral surface of the stomach is called the greater curvature; the concave medial border is the lesser curvature. Two fatty mesenteries (peritoneal folds) called omenta hold the stomach in place. The lesser omentum extends from the liver to the lesser curvature. The greater omentum runs from the greater curvature to the posterior abdominal wall.

Adaptations of Stomach Wall

The wall of the stomach is made of the same four tissue layers as most of the rest of the GI tract, but with adaptations to the mucosa and muscularis externa for the unique functions of this organ. In addition to the typical circular and longitudinal smooth muscle layers, the muscularis externa has an inner oblique smooth muscle layer that runs diagonally around the organ. As a result, in addition to moving food through the GI tract, the stomach can more vigorously churn and mix food, mechanically breaking it down into smaller particles.

Gatric pit. This work by Cenveo is licensed under a Creative Commons Attribution 3.0 United States (http://creativecommons.org/licenses/by/3.0/us/).

Histology section of a gastric pit. This work is licensed under a Creative Commons Attribution-Noncommercial-Share Alike 3.0 License© copyright 2010 Regents of the University of Michigan.

Millions of deep gastric pits in the epithelium lead into gastric glands, which secrete gastric juice. The walls of the gastric pits are made up primarily of epithelial cells. The gastric glands are made up of different types of cells. Glands of the cardia and pylorus are composed primarily of mucus-secreting cells. Cells that make up the pyloric antrum secrete mucus and a number of hormones, including gastrin. The much larger glands of the fundus and body of the stomach, the site of most chemical digestion, produce most of the gastric secretions. These glands are made up of a variety of secretory cells, including mucous neck, parietal, chief, and enteroendocrine cells (G-cells).

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Structure	Action	Outcome
Muscularis Externa	Mixing wavesPeristalsis	Forms chyme by liquefying food and mixing it with gastric juicePropels chyme through pyloric sphincter
Pyloric sphincter	Controls passage of chyme from the stomach to the duodenum	Delivers chyme to the intestine at a rate optimal for digestion and absorption; prevents chyme from flowing back to stomach from duodenum
Chief cells	Secrete pepsinogenSecrete gastric lipase	Pepsin (activated form) breaks proteins down into peptidesBreaks down triglycerides into fatty acids and monoglycerides
G cells	Secrete gastrin	Activates secretion of HCl by parietal cells and pepsinogen by chief cells; contracts lower esophageal sphincter, enhances stomach motility, and relaxes pyloric sphincter
Parietal cells	Secrete HClSecrete intrinsic factor	Kills food microbes; denatures proteins, transforms pepsinogen into pepsinEnables vitamin B12 absorption for red blood cell formation
Surface mucous cells and mucous neck cells	Secrete mucusAbsorption	Protects stomach wall from digestive processesAllows limited amount of water, ions, short-chain fatty acids, and certain drugs to enter bloodstream

The secretion of gastric juice is controlled by nerves, hormones, and the presence of products of digestion. Stimuli from smell, sight and taste as well as food in the oral cavity, stomach, and small intestine activate or inhibit gastric juice production. This is why the three phases of gastric secretion are called the cephalic, gastric, and intestinal phases. However, once gastric secretion begins, all three phases can occur simultaneously.

The cephalic (reflex) phase of gastric secretion, which lasts just a few minutes, takes place before food enters the stomach. The smell, taste, sight, or thought of food triggers this phase. For example, impulses from receptors in taste buds or the nose are relayed to the brain, which returns signals that increase gastric secretion to prepare the stomach for digestion. This enhanced secretion is a conditioned reflex, meaning it occurs only if we like or want a particular food. Depression and loss of appetite can suppress the cephalic reflex.

The gastric phase of secretion lasts three to four hours and is set in motion by local neural and hormonal mechanisms triggered by the entry of food into the stomach. For example, stomach distension activates stretch receptors that stimulate parasympathetic neurons to release acetylcholine, which then provokes increased secretion of gastric juice. Partially digested proteins, caffeine, and rising pH stimulate the release of gastrin from enteroendocrine G cells, which in turn provokes parietal cells to increase their production of HCl and increase motility through the stomach by altering sphincter function. The presence of proteins in the stomach raises pH, which stimulates the increased gastrin and HCl release needed to create an acidic environment for protein digestion.

The stomach participates in virtually all digestive activities with the exception of ingestion and defecation. In addition to mechanical and chemical digestion, the stomach absorbs some fat-soluble substances, including alcohol and aspirin.

The small intestine is a convoluted tube that begins just distal to the pyloric sphincter of the stomach and then loops through the central and inferior region of the abdomen before ending at the ileocecal valve, where it merges with the large intestine. The small intestine is the primary digestive organ in the body. Not only is it the part of the GI tract where digestion is completed, it is also where the majority of absorption occurs.

Although the small intestine is the longest part of the GI tract, its diameter is about half that of the large intestine, averaging a little over one inch (2.5 cm). When we are alive, the small intestine is more than 3 meters (10 feet) long – the size of a one-story building. Its length provides expansive surface area necessary for digestion and absorption. However, circular folds, villi, and microvilli add even more surface area. With loss of muscle tone after death, the folds of the small intestine relax, extending it to about 20 feet in length.

This work by Cenveo is licensed under a Creative Commons Attribution 3.0 United States (http://creativecommons.org/licenses/by/3.0/us/).

Each day, the alimentary canal processes up to 10 liters of food, liquids, and GI secretions; of which, only about one liter enters the large intestine. Almost all ingested food and drink, 80 percent of electrolytes, and most of the water are absorbed in the small intestine. The entire small intestine is involved in absorption, but most absorption occurs before chyme reaches the ileum. Absorption in the ileum primarily involves the recycling of bile salts. The absorptive capacity of the alimentary canal is amazing. By the time chyme passes from the ileum into the large intestine, it is essentially indigestible food residue (mainly plant fibers like cellulose) some water, and millions of bacteria.

The absorption of most nutrients through the mucosa of the intestinal villi occurs via active transport mechanisms that are driven directly or indirectly by metabolic energy. These nutrients enter the capillary blood in the villus and travel to the liver via the hepatic portal vein. An exception is certain lipids, which undergo passive absorption via diffusion and then enter the modified lymph duct in the villus (called a lacteal), to be transported to the blood in lymphatic fluid. Substances cannot be absorbed between the epithelial cells of the intestinal mucosa, because these cells connect with tight junctions. This is why substances can only enter blood capillaries by passing through the epithelial cells and into the interstitial fluid.

The large intestine is the terminal part of the gastrointestinal tract. The primary digestive function of this organ is to finish absorption, produce some vitamins, form feces, resorb water and eliminate feces from the body.

The large intestine runs from the cecum, where it attches to the ileum, to the anus. It borders the small intestine on three sides. Despite its being around half as long as the small intestine – 4.9 feet versus 10 feet (1.5 – 3 meters) – it is called the large intestine because it is more than twice the diameter of the small intestine, 2.5 inches versus one inch (6 cm versus 2.5 cm). The large intestine is tethered to the posterior abdominal wall by the mesocolon, a double layer of peritoneal membrane.

The large intestine is subdivided into four main regions: the cecum, the colon, the rectum, and the anus. The ileocecal valve, located at the opening between the ileum in the small intestine and the large intestine, controls the flow of chyme from the small to the large intestine.

Large Intestine Anatomical Structures

Like the small intestine, the mucosa of the large intestine has intestinal glands that contain both absorptive and goblet cells. However, there are several notable differences between the walls of the large and small intestines. For example, other than the anal canal, the mucosa of the colon is simple columnar epithelium. In addition, the wall of the large intestine has no circular folds, no villi, and essentially no enzyme-secreting cells. This is because most nutrients are already absorbed before chyme enters the large intestine. The large intestinal wall does have thicker mucosa and deeper – and more abundant – glands that contain a vast number of goblet cells. These goblet cells secrete mucus that eases the movement of feces and protects the intestine from the effects of the acids and gases produced by enteric bacteria.

Anatomical structures of the large intestine. This work by Cenveo is licensed under a Creative Commons Attribution 3.0 United States (http://creativecommons.org/licenses/by/3.0/us/).

The stratified squamous epithelial mucosa of the anal canal joins with the skin around the anus. This mucosa varies considerably from that of the rest of the colon to accommodate the increased abrasion in this region. The anal canal's mucous membrane is organized in longitudinal folds called anal columns that house a grid of veins. Depressions between the anal columns, called anal sinuses, secrete mucus when they are crowded by feces. This facilitates defecation. The pectinate line is a horizontal, jagged band that runs alongside the inferior margins of the anal sinuses. The mucosa superior to this line is fairly insensitive to pain, while the area inferior to this line is very pain-sensitive. The difference in pain response is due to the fact that the superior region is innervated by visceral sensory fibers, and the inferior region is innervated by somatic sensory fibers. There are two superficial venous plexuses in the anal canal – one with the anus and the other with the anal columns. Inflammation and distension of these (hemorrhoidal) veins causes hemorrhoids, an itchy condition caused by the swelling of these vessels.

Three features are unique to the large intestine: teniae coli, haustra, and epiploic appendages. The teniae coli are three bands of smooth muscle that make up the longitudinal muscle layer of the muscularis externa of the large intestine, except at its terminal end in the rectum. Tonic contractions of the teniae coli bunch up the colon into a succession of pouches called haustra, which are responsible for the wrinkled appearance of the colon. Attached to the teniae coli are small, fat-filled sacs of visceral peritoneum called epiploic appendages (omental appendices). These fatty pouches of peritoneum found in the serosa from the transverse colon through the sigmoid colon.

Although the rectum and anal canal have no teniae coli or haustra, they do have well-developed layers of muscularis externa muscle that create the strong contractions needed for defecation.

Large Intestine Gross Anatomy

The first part of the large intestine is the cecum, a small sac-like region that is suspended inferior to the ileocecal valve. This cecum is about 2.4 inches long. The appendix or vermiform appendix (vermiform = “worm-shaped”, and appendix = “appendage”) is a winding, coiled tube that attaches to the cecum. This 2-7 cm (~3 inch) long appendix contains lymphoid tissue and plays an important role in immunity. Nevertheless, its twisted anatomy provides a haven for the accumulation and multiplication of enteric bacteria. The mesoappendix, the mesentery of the appendix, tethers it to the inferior part of the mesentery of the ileum.

Gross anatomy of the large intestine. This work by Cenveo is licensed under a Creative Commons Attribution 3.0 United States (http://creativecommons.org/licenses/by/3.0/us/).

The end of the cecum joins with the colon, a long tube with several distinct areas. The ascending colon runs up the right side of the abdomen. At the inferior surface of the liver, it takes a right-angle turn, forming the right colic (hepatic) flexure and becoming the transverse colon. The transverse colon runs across to the left side of the abdomen. It then bends sharply at a point immediately anterior to the spleen, forming the left colic (splenic) flexure. As the descending colon, it runs down the left side of the posterior abdominal wall. After entering the pelvis inferiorly, it becomes the s-shaped sigmoid colon, which extends medially to the midline. Most of the colon is between the peritoneal membrane and the body wall, except for the intraperitoneal transverse and sigmoid colons, which are tethered to the posterior abdominal wall by mesocolons.

The sigmoid colon joins the rectum in the pelvis, near the third sacral vertebra. The rectum is the final 8 inches (20 cm) of the alimentary canal. It extends anterior to the sacrum and coccyx. Even though rectum is Latin for "straight," this structure has three lateral bends that create a trio of internal transverse folds called the rectal valves. These valves allow passing of gas (flatus) while preventing the simultaneous passage of feces.

The last part of the large intestine is the anal canal, which is located in the perineum, completely outside the abdominopelvic cavity. This 1 inch (3 cm) long structure opens to the exterior of the body at the anus. The anal canal includes two sphincters. The involuntary internal anal sphincter is made of smooth muscle; the voluntary external anal sphincter is skeletal muscle. Except when defecating, these two sphincters are usually closed.

There are many species of bacteria that populate the large intestines. They digest food products for which we do not have enzymes (such as plant materials) and we absorb some of the nutrient products. They can also produce some vitamins like vitamin K and B vitamins. A byproduct of bacterial fermentation (digestion) is gas (flatus).

Although the bacteria provide additional nutrients from the food we ingest, they can also infect us. Because of the large and diverse bacterial population that resides in the large intestine, the large intestine also contains plentiful lymphatic tissue to protect us from potentially harmful effects of resident bacteria.

Most bacteria that migrate to the cecum from the small intestine have already been killed by lysozyme and other antibacterial molecules, HCl, and protein-digesting enzymes. Those that are still living, along with bacteria that come into the alimentary canal through the anus, are referred to as the large intestine's (enteric) bacterial flora. The more than 700 species of bacterial flora in the colon participate in chemical digestion and absorption. The large intestine is also home to a number of viruses and protozoans, at least 20 of which are known pathogens.

Most enteric bacteria are nonpathogenic commensals (also called symbiotic, wityh benefit to both organisms) that cause no harm as long as they stay in the gut lumen. A refined system prevents these bacteria from crossing the mucosal barrier. First, certain bacterial components activate the release of chemicals by the mucosa's epithelial cells, which recruit immune cells, especially dendritic cells, into the mucosa. Dendritic cells open the tight junctions between epithelial cells and extend probes into the lumen to evaluate the microbial antigens. The dendritic cells then travel to neighboring lymphoid follicles in the mucosa and hand over the antigens to T cells. This triggers an IgA antibody-mediated response in the lumen that blocks the commensals from infiltrating the mucosa and setting off a far greater, widespread systematic reaction.

The major digestive role of the large intestine involves propulsion--pushing fecal matter toward the anus and then out of the body. Chyme, which stays in the large intestine for 12 to 24 hours, contains few nutrients. Enteric bacteria are responsible for a small amount of digestion. The bacterial flora create vitamins required for normal metabolism, such as certain B vitamins and vitamin K. Most of the remaining water and some electrolytes (especially sodium and chloride) are recycled.