Muscles

Animals use muscles to convert the chemical energy of ATP into mechanical work. Three different kinds of muscles are found in vertebrate animals

Anatomy of Skeletal Muscle

A single skeletal muscle, such as the triceps muscle, is attached at its

As the triceps contracts, the insertion is pulled toward the origin and the arm is straightened or extended at the elbow. Thus the triceps is an extensor. Because skeletal muscle exerts force only when it contracts, a second muscle - a flexor - is needed to flex or bend the joint. The biceps muscle is the flexor of the lower arm. Together, the biceps and triceps make up an antagonistic pair of muscles. Similar pairs, working antagonistically across other joints, provide for almost all the movement of the skeleton.

The Muscle Fiber

Skeletal muscle is made up of thousands of cylindrical muscle fibers often running all the way from origin to insertion. The fibers are bound together by connective tissue through which run blood vessels and nerves.

The number of fibers is probably fixed early in life. Increased strength and muscle mass comes about through an increase in the thickness of the individual fibers and increase in the amount of connective tissue.

Seen from the side under the microscope, skeletal muscle fibers show a pattern of cross banding, which gives rise to the other name: striated muscle.

Each muscle fibers contains: The multiple nuclei arise from the fact that each muscle fiber develops from the fusion of many cells (called myoblasts). Because a muscle fiber is not a single cell, its parts are often given special names such as although this tends to obscure the essential similarity in structure and function of these structures and those found in other cells.

The

The striated appearance of the muscle fiber is created by a pattern of alternating Each myofibril is made up of arrays of parallel filaments.

The anatomy of a sarcomere

The entire array of thick and thin filaments between the Z lines is called a sarcomere. Shortening of the sarcomeres in a myofibril produces the shortening of the myofibril and, in turn, of the muscle fiber of which it is a part. [This electron micrograph of a single sarcomere was kindly provided by Dr. H. E. Huxley.]

Activation of Skeletal Muscle

The contraction of skeletal muscle is controlled by the nervous system. The Dying Lioness (an Assyrian relief dating from about 650 B.C. and supplied through the courtesy of The Trustees of the British Museum) shows this vividly. Injury to the spinal cord has paralyzed the otherwise undamaged hind legs.

In this respect, skeletal muscle differs from smooth and cardiac muscle. Both cardiac and smooth muscle can contract without being stimulated by the nervous system. Nerves of the autonomic branch of the nervous system lead to both smooth and cardiac muscle, but their effect is one of moderating the rate and/or strength of contraction.

The Neuromuscular Junction

Nerve impulses (action potentials) traveling down the motor neurons of the sensory-somatic branch of the nervous system cause the skeletal muscle fibers at which they terminate to contract. The junction between the terminal of a motor neuron and a muscle fiber is called the neuromuscular junction. It is simply one kind of synapse. (The neuromuscular junction is also called the myoneural junction.)

The terminals of motor axons contain thousands of vesicles filled with acetylcholine (ACh).

When an action potential reaches the axon terminal, hundreds of these vesicles discharge their ACh onto a specialized area of postsynaptic membrane on the fiber. This area contains a cluster of transmembrane channels that are opened by ACh and let sodium ions (Na+) diffuse in.

The interior of a resting muscle fiber has a resting potential of about -95 mV. The influx of sodium ions reduces the charge, creating an end plate potential. If the end plate potential reaches the threshold voltage (approximately -50 mV), sodium ions flow in with a rush and an action potential is created in the fiber. The action potential sweeps down the length of the fiber just as it does in an axon.

No visible change occurs in the muscle fiber during (and immediately following) the action potential. This period, called the latent period, lasts from 3-10 msec.

Before the latent period is over,

The brief (1-2 msec) period needed to restore the resting potential is called the refractory period.

The latent period is followed by contraction. Contraction, like the action potential, is all-or-none. Either the fiber contracts maximally or it doesn't contract at all. The process of contracting takes some 50 msec; relaxation of the fiber takes another 50-100 msec. Because the refractory period is so much shorter than the time needed for contraction and relaxation, the fiber can be maintained in the contracted state so long as it is stimulated frequently enough (e.g., 50 stimuli per second). Such sustained contraction is called tetanus. As we normally use our muscles, the individual fibers go into tetanus for brief periods rather than simply undergoing single twitches.

The Sliding-Filament Model

Each molecule of myosin in the thick filaments contains a globular subunit called the myosin head. The myosin heads have binding sites for

Activation of the muscle fiber causes the myosin heads to bind to actin. An allosteric change occurs which draws the thin filament a short distance (~10 nm) past the thick filament. Then the linkages break (for which ATP is needed) and reform farther along the thin filament to repeat the process. As a result, the filaments are pulled past each other in a ratchetlike action. There is no shortening, thickening, or folding of the individual filaments.

Electron microscopy supports this model: As a muscle contracts, As a muscle is stretched, the width of the I bands and H zones increases, but there is still no change in the width of the A band.

Coupling Excitation to Contraction

Calcium ions (Ca2+) link action potentials in a muscle fiber to contraction.

Isotonic versus Isometric Contractions

If a stimulated muscle is held so that it cannot shorten, it simply exerts tension. This is called an isometric ("same length") contraction. If the muscle is allowed to shorten, the contraction is called isotonic ("same tension").

Motor Units

All motor neurons leading to skeletal muscles have branching axons, each of which terminates in a neuromuscular junction with a single muscle fiber. Nerve impulses passing down a single motor neuron will thus trigger contraction in all the muscle fibers at which the branches of that neuron terminate. This minimum unit of contraction is called the motor unit.

The size of the motor unit is small in muscles over which we have precise control. Examples:

Although the response of a motor unit is all-or-none, the strength of the response of the entire muscle is determined by the number of motor units activated.

Even at rest, most of our skeletal muscles are in a state of partial contraction called tonus. Tonus is maintained by the activation of a few motor units at all times even in resting muscle. As one set of motor units relaxes, another set takes over.

Fueling Muscle Contraction

ATP is the immediate source of energy for muscle contraction. Although a muscle fiber contains only enough ATP to power a few twitches, its ATP "pool" is replenished as needed. There are three sources of high-energy phosphate to keep the ATP pool filled.

Creatine phosphate

The phosphate group in creatine phosphate is attached by a "high-energy" bond like that in ATP. Creatine phosphate derives its high-energy phosphate from ATP and can donate it back to ADP to form ATP.

Creatine phosphate + ADP <--> creatine + ATP

The pool of creatine phosphate in the fiber is about 10 times larger than that of ATP and thus serves as a modest reservoir of ATP.

Glycolysis

Skeletal muscle fibers contain about 1% glycogen. The muscle fiber can degrade this glycogen by glycolysis. Glycolysis yields two molecules of ATP for each pair of lactic acid molecules produced. Not much, but enough to keep the muscle functioning if it fails to receive sufficient oxygen to meet its ATP needs by respiration. However, this source is limited and eventually the muscle must depend on cellular respiration.

Cellular respiration

Cellular respiration not only is required to meet the ATP needs of a muscle engaged in prolonged activity (thus causing more rapid and deeper breathing), but is also required afterwards to enable the body to resynthesize glycogen from the lactic acid produced earlier (deep breathing continues for a time after exercise is stopped). The body must repay its oxygen debt.

Cardiac Muscle

Cardiac or heart muscle resembles skeletal muscle in some ways: it is striated and each cell contains sarcomeres with sliding filaments of actin and myosin.

However, cardiac muscle has a number of unique features that reflect its function of pumping blood.
This electron micrograph (reproduced with permission from Keith R. Porter and Mary A. Bonneville, An Introduction to the Fine Structure of Cells and Tissues, 4th ed., Lea & Febiger, Philadelphia, 1973) shows an adherens junction and several of the other features listed here.

Smooth Muscle

Smooth muscle is made of single, spindle-shaped cells. It gets its name because no striations are visible in them. Nonetheless, each smooth muscle cell contains thick (myosin) and thin (actin) filaments that slide against each other to produce contraction of the cell. The thick and thin filaments are anchored near the plasma membrane (with the help of intermediate filaments)).

Smooth muscle (like cardiac muscle) does not depend on motor neurons to be stimulated. However, motor neurons (of the autonomic system) reach smooth muscle and can stimulate it (or inhibit it - depending on the receptors present on the cell surface) by the neurotransmitter they release (e.g. noradrenaline).

Smooth muscle can also be made to contract

The contraction of smooth muscle tends to be slower than that of striated muscle. It also is often sustained for long periods. This, too, is called tonus but the mechanism is not like that in skeletal muscle.

Muscle Diseases

The Muscular Dystrophies (MD)

Together myosin, actin, tropomyosin, and troponin make up over three-quarters of the protein in muscle fibers. Some two dozen other proteins make up the rest. These serve such functions as attaching and organizing the filaments in the sarcomere and connecting the sarcomeres to the plasma membrane and the extracellular matrix. Mutations in the genes encoding these proteins may produce defective proteins and resulting defects in the muscles.

Among the most common of the muscular dystrophies are those caused by mutations in the gene for dystrophin.

The gene for dystrophin is huge, containing 79 exons spread out over 2.3 million base pairs of DNA. Thus this single gene represents about 0.1% of the entire human genome (3 x 109 bp) and is almost half the size of the entire genome of E. coli!

The gene for dystrophin is on the X chromosome, so these two diseases strike males in a typical X-linked pattern of inheritance.

Myasthenia Gravis

Myasthenia gravis is an autoimmune disorder affecting the neuromuscular junction. Patients have smaller end plate potentials (EPPs) than normal. With repeated stimulation, the EPPs become too small to trigger further action potentials and the fiber ceases to contract. Administration of an inhibitor of acetylcholinesterase temporarily can restore contractility by allowing more ACh to remain at the site.

Patients with myasthenia gravis have only 20% or so of the number of ACh receptors found in normal neuromuscular junctions. This loss appears to be caused by antibodies directed against the receptors. Some evidence:

The reason some people develop autoimmune antibodies against the ACh receptor is unknown.

The Cardiac Myopathies

Cardiac muscle, like skeletal muscle, contains many proteins in addition to actin and myosin. Mutations in the genes for these may cause the wall of the heart to become weakened and, in due course, enlarged. Among the genes that have been implicated in these diseases are those encoding:

The severity of the disease varies with the particular mutation causing it (over 100 have been identified so far) . Some mutations are sufficiently dangerous that they can lead to sudden catastrophic heart failure in seemingly healthy and active young adults.

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13 June 1999