PHYSIOLOGY OF MUSCLES. PHYSIOLOGY OF SPINAL CORD.
The ability to use chemical energy to produce force and movement is present to a limited extent in most cells. It is, however, in muscle cells that this process has become dominant. The primary function of these specialized cells is to generate the forces and movements used in the regulation of the internal environment and to produce movements in the external environment. In humans, the ability to communicate, whether by speech, writing, or artistic expression, also depends on muscle contractions. Indeed, it is only by controlling the activity of muscles that the human mind ultimately expresses itself.
Three types of muscle tissue can be identified on the basis of structure, contractile properties, and control mechanisms: (1) skeletal muscle, (2) smooth muscle, and (3) cardiac muscle. Most skeletal muscle, as the name implies, is attached to bone, and its contraction is responsible for supporting and moving the skeleton. The contraction of skeletal muscle is initiated by impulses in the neurons to the muscle and is usually under voluntary control. Sheets of smooth muscle surround various hollow organs and tubes, including the stomach, intestines, urinary bladder, uterus, blood vessels, and airways in the lungs. Contraction of the smooth muscle surrounding hollow organs may propel the luminal contents through the organ, or it may regulate internal flow by changing the tube diameter. In addition, small bundles of smooth-muscle cells are attached to the hairs of the skin and iris of the eye. Smooth-muscle contraction is controlled by the autonomic nervous system, hormones, autocrine/paracrine agents, and other local chemical signals.
Some smooth muscles contract spontaneously, however, even in the absence of such signals. In contrast to skeletal muscle, smooth muscle is not normally under voluntary control. Cardiac muscle is the muscle of the heart. Its contraction
propels blood through the circulatory system. Like smooth muscle, it is regulated by the autonomic nervous system, hormones, and autocrine/paracrine agents, and certain portions of it can undergo spontaneous contractions. Although there are significant differences in these three types of muscle, the force-generating mechanism is similar in all of them.
A single skeletal-muscle cell is known as a muscle fiber. Each muscle fiber is formed during development by the fusion of a number of undifferentiated, mononucleated cells, known as myoblasts, into a single cylindrical, multinucleated cell. Skeletal muscle differentiation is completed around the time of birth, and these differentiated fibers continue to increase in size during growth from infancy to adult stature, but no new fibers are formed from myoblasts. Adult skeletalmuscle fibers have diameters between 10 and 100 _m and lengths that may extend up to 20 cm. If skeletal-muscle fibers are destroyed after birth as a result of injury, they cannot be replaced by the division of other existing muscle fibers. New fibers can be formed, however, from undifferentiated cells known as satellite cells, which are located adjacent to the muscle fibers and undergo differentiation similar to that followed by embryonic myoblasts. This capacity for forming new skeletal-muscle fibers is considerable but will not restore a severely damaged muscle to full strength. Much of the compensation for a loss of muscle tissue occurs through an increase in the size of the remaining muscle fibers.
The term muscle refers to a number of muscle fibers bound together by connective tissue. The relationship between a single muscle fiber and a muscle is analogous to that between a single neuron and a nerve, which is composed of the axons of many neurons. Muscles are usually linked to bones by bundles of collagen fibers known as tendons, which are located at each end of the muscle.
In some muscles, the individual fibers extend the entire length of the muscle, but in most, the fibers are shorter, often oriented at an angle to the longitudinal axis of the muscle. The transmission of force from muscle to bone is like a number of people pulling on a rope, each person corresponding to a single muscle fiber and the rope corresponding to the connective tissue and tendons.
Some tendons are very long, with the site of tendon attachment to bone far removed from the end of the muscle. For example, some of the muscles that move the fingers are in the forearm, as one can observe by wiggling one’s fingers and feeling the movement of the muscles in the lower arm. These muscles are connected to the fingers by long tendons.
The most striking feature seen when observing skeletal- or cardiac-muscle fibers through a light microscope is a series of light and dark bands perpendicular to the long axis of the fiber. Because of this characteristic banding, both types are known as striated muscle. Smoothmuscle cells do not show a banding pattern. The striated pattern in skeletal and cardiac fibers results from the arrangement of numerous thick and thin filaments in the cytoplasm into approximately cylindrical bundles (1 to 2 _m in diameter) known as myofibrils. Most of the cytoplasm of a fiber is filled with myofibrils, each of which extends from one end of the fiber to the other and is linked to the tendons at the ends of the fiber.
Skeletal-muscle fibers viewed through a light microscope. Each bracket at the left indicates one muscle fiber. Arrow indicates a blood vessel containing red blood cells.
The thick and thin filaments in each myofibril are arranged in a repeating pattern along the length of the myofibril. One unit of this repeating pattern is known as a sarcomere (Greek, sarco, muscle; mere, small). The thick filaments are composed almost entirely of the contractile protein myosin. The thin filaments (which are about half the diameter of the thick filaments) contain the contractile protein actin, as well as to two other proteins— troponin and tropomyosin—that play important roles in regulating contraction, as we shall see.
The thick filaments are located in the middle of each sarcomere, where their orderly parallel arrangement produces a wide, dark band known as the A band. Each sarcomere contains two sets of thin filaments, one at each end. One end of each thin filament is anchored to a network of interconnecting proteins known as the Z line, whereas the other end overlaps a portion of the thick filaments. Two successive Z lines define the limits of one sarcomere. Thus, thin filaments from two adjacent sarcomeres are anchored to the two sides of each Z line.
A light band, known as the I band, lies between the ends of the A bands of two adjacent sarcomeres and contains those portions of the thin filaments that do not overlap the thick filaments. It is bisected by the Z line. Two additional bands are present in the A-band region of each sarcomere. The H zone is a narrow light band in the center of the A band. It corresponds to the space between the opposing ends of the two sets of thin filaments in each sarcomere; hence, only thick filaments, specifically their central parts, are found in the H zone. A narrow, dark band in the center of the H zone is known as the M line and corresponds to proteins that link together the central region of the thick filaments. In addition, filaments composed of the protein titin extend from the Z line to the M line and are linked to both the M-line proteins and the thick filaments. Both the M-line linkage between thick filaments and the titin filaments act to maintain the regular array of thick filaments in the middle of each sarcomere. Thus, neither the thick nor the thin filaments are free-floating.
A cross section through the A bands, shows the regular, almost crystalline, arrangement of overlapping thick and thin filaments. Each thick filament is surrounded by a hexagonal array of six thin filaments, and each thin filament is surrounded by a triangular arrangement of three thick filaments. Altogether there are twice as many thin as thick filaments in the region of filament overlap.
The space between overlapping thick and thin filaments is bridged by projections known as cross bridges. These are portions of myosin molecules that extend from the surface of the thick filaments toward the thin filaments. During muscle contraction, the cross bridges make contact with the thin filaments and exert force on them. The term contraction, as used in muscle physiology, does not necessarily mean “shortening”; rather it refers only to the turning on of the force-generating sites— the cross bridges—in a muscle fiber. Following contraction, the mechanisms that initiate force generation are turned off, and tension declines, allowing relaxation of the muscle fiber.
(a) Numerous myofibrils in a single skeletal-muscle fiber (arrows in upper right corner indicate mitochondria between the myofibrils). (b) High magnification of a sarcomere within a myofibril (arrow at the right of A band indicates end of a thick filament). (c) Arrangement of the thick and thin filaments in the sarcomere shown in b.
Sliding-Filament Mechanism
When force generation produces shortening of a skeletal-muscle fiber, the overlapping thick and thin filaments in each sarcomere move past each other, propelled by movements of the cross bridges. During this shortening of the sarcomeres, there is no change in the lengths of either the thick or thin filaments. This is known as the sliding-filament mechanism of muscle contraction.
During shortening, each cross bridge attached to a thin filament moves in an arc much like an oar on a boat. This swiveling motion of many cross bridges forces the thin filaments at either end of the A band toward the center of the sarcomere, thereby shortening the sarcomere. One stroke of a cross bridge produces only a very small movement of a thin filament relative to a thick filament. As long as a muscle fiber remains “turned on,” however, each cross bridge repeats its swiveling motion many times, resulting in large displacements of the filaments. Let us look more closely at these events. Amuscle fiber’s ability to generate force and movement depends on the interactions of the two so-called contractile proteins—myosin in the thick filaments and actin in the thin filaments—and energy provided by ATP.
An actin molecule is a globular protein composed of a single polypeptide that polymerizes with other actins to form two intertwined helical chains that make up the core of a thin filament. Each actin molecule contains a binding site for myosin. The myosin molecule, on the other hand, is composed of two large polypeptide heavy chains and four smaller light chains. These polypeptides combine to form a molecule that consists of two globular heads (containing heavy and light chains) and a long tail formed by the two intertwined heavy chains.
The tail of each myosin molecule lies along the axis of the thick filament, and the two globular heads extend out to the sides, forming the cross bridges. Each globular head contains two binding sites, one for actin and one for ATP. The ATP binding site also serves as an enzyme—an ATPase that hydrolyzes the bound ATP. The myosin molecules in the two ends of each thick filament are o riented in opposite directions, such that their tail ends are directed toward the center of the filament.
The sliding of thick filaments past overlapping thin filaments produces shortening with no change in thick or thin filament length. The I band and H zone have, however, decreased.
Cross bridges in the thick filaments bind to actin in the thin filaments and undergo a conformational change that propels the thin filaments toward the center of a sarcomere. (Only 2 of the approximately 200 cross bridges in each thick filament are shown.)
Because of this arrangement, the power strokes of the cross bridges move the attached thin filaments at the two ends of the sarcomere toward the center during shortening.
(a) The heavy chains of myosin molecules form the core of a thick filament. The myosin molecules are oriented in opposite directions in either half of a thick filament. (b) Structure of a myosin molecule. The two globular heads of each myosin molecule extend from the sides of a thick filament forming a cross bridge.
The sequence of events that occurs between the time a cross bridge binds to a thin filament, moves, and then is set to repeat the process is known as a cross-bridge cycle. Each cycle consists of four steps: (1) attachment of the cross bridge to a thin filament, (2) movement of the cross bridge, producing tension in the thin filament, (3) detachment of the cross bridge from the thin filament, and (4) energizing the cross bridge so that it can again attach to a thin filament and repeat the cycle. Each cross bridge undergoes its own cycle of movement independently of the other cross bridges, and at any one instant during contraction only a portion of the cross bridges overlapping a thin filament are attached to the thin filaments and producing tension, while others are in a detached portion of their cycle.
At the conclusion (step 4) of the preceding cycle, the ATP bound to myosin is split, releasing chemical energy which results in a conformational change in the cross bridge. This produces an energized form of myosin (M*) to which the products of ATP hydrolysis, ADP and inorganic phosphate (Pi), are still bound. This storage of energy in myosin is analogous to the storage of potential energy in a stretched spring.
A new cross-bridge cycle begins with the binding of an energized myosin cross bridge to actin (A) in a thin filament (step 1):
The binding of energized myosin to actin triggers the release of the strained conformation of the energized bridge, which produces the movement of the bound cross bridge (step 2) and the release of ADP and Pi:
This sequence of energy storage and release by myosin is analogous to the operation of a mousetrap: Energy is stored in the trap by cocking the spring (ATP hydrolysis) and released after springing the trap (binding to actin). During the cross-bridge movement, myosin is bound very firmly to actin, and this linkage must be broken in order to allow the cross bridge to be reenergized and repeat the cycle. The binding of a molecule of ATP to myosin breaks the link between actin and myosin (step 3):
The dissociation of actin and myosin by ATP is an example of allosteric regulation of protein activity. The binding of ATP at one site on myosin decreases myosin’s affinity for actin bound at another site. Thus, ATP is acting as a modulator molecule controlling the binding of actin to myosin. Note that ATP is not split in this step; that is, it is not acting as an energy source but only as a modulator molecule that produces an allosteric modulation of the myosin head that weakens the binding of myosin to actin.
Then, following the dissociation of actin and myosin, the ATP bound to myosin is split (step 4), thereby re-forming the energized state of myosin, which caow reattach to a new site on the actin filament and repeat the cycle. Note that the release of energy by the hydrolysis of ATP (step 4) and the movement of the cross bridge (step 2) are not simultaneous events. To summarize, ATP performs two distinct roles in the cross-bridge cycle: (1) The energy released from ATP hydrolysis ultimately provides the energy for cross-bridge movement, and (2) ATP binding (not hydrolysis) to myosin breaks the link formed between actin and myosin during the cycle, allowing the cycle to be repeated.
The importance of ATP in dissociating actin and myosin during step 3 of a cross-bridge cycle is illustrated by rigor mortis, the stiffening of skeletal muscles that begins several hours after death and is complete after about 12 h. The ATP concentration in cells, including muscle cells, declines after death because the nutrients and oxygen required by the metabolic pathways to form ATP are no longer supplied by the circulation. In the absence of ATP, nonenergized cross bridges can bind to actin, but the subsequent movement of the cross bridge and the breakage of the link between actin and myosin do not occur because these events require ATP. The thick and thin filaments become bound to each other by immobilized cross bridges, producing a rigid condition in which the thick and thin filaments cannot be passively pulled past each other. The stiffness of rigor mortis disappears about 48 to 60 h after death as a result of the disintegration of muscle tissue.
Roles of Troponin, Tropomyosin, and Calcium in Contraction
Since every muscle fiber contains all the ingredients necessary for cross-bridge activity (actin, myosin, and ATP) the question arises: Why are muscles not in a continuous state of contractile activity? The answer is that in a resting muscle fiber, the cross bridges are prevented from interacting with actin by two proteins, troponin and tropomyosin, which, as noted earlier, are located on thin filaments.
Tropomyosin is a rod-shaped molecule composed of two intertwined polypeptides with a length approximately equal to that of seven actin molecules. Chains of tropomyosin molecules are arranged end to end along the actin thin filament. These tropomyosin molecules partially cover the myosin-binding site on each actin molecule, thereby preventing the cross bridges from making contact with actin. Each tropomyosin molecule is held in this blocking position by troponin, a smaller, globular protein that is bound to both tropomyosin and actin. One molecule of troponin binds to each molecule of tropomyosin and regulates the access to myosin-binding sites on the seven actin molecules in contact with tropomyosin.
(a) Molecule of troponin bound to a molecule of tropomyosin. (b) Two chains of tropomyosin on a thin filament regulate access of cross bridges to binding sites on actin.
Having described the system that prevents crossbridge activity and thus keeps a muscle fiber in a resting state, we caow ask: What enables cross bridges to bind to actin and begin cycling? For this to occur, tropomyosin molecules must be moved away from their blocking positions on actin. This happens when calcium binds to specific binding sites on troponin (not tropomyosin). The binding of calcium produces a change in the shape of troponin, which through troponin’s linkage to tropomyosin, drags tropomyosin away from the myosin-binding site on each actin molecule. Conversely, removal of calcium from troponin reverses the process, turning off contractile activity.
Thus, cytosolic calcium-ion concentration determines the number of troponin sites occupied by calcium, which in turn determines the number of actin sites available for cross-bridge binding. Changes in cytosolic calcium concentration are controlled by electrical events in the muscle plasma membrane, which we now discuss.
Excitation-Contraction Coupling
Excitation-contraction coupling refers to the sequence of events by which an action potential in the plasma membrane of a muscle fiber leads to cross-bridge activity by the mechanisms just described. The skeletalmuscle plasma membrane is an excitable membrane capable of generating and propagating action potentials by mechanisms similar to those described for nerve cells. An action potential in a skeletalmuscle fiber lasts 1 to 2 ms and is completed before any signs of mechanical activity begin. Once begun, the mechanical activity following an action potential may last 100 ms or more. The electrical activity in the plasma membrane does not directly act upon the contractile proteins but instead produces a state of increased cytosolic calcium concentration, which continues to activate the contractile apparatus long after the electrical activity in the membrane has ceased. In a resting muscle fiber, the concentration of free, ionized calcium in the cytosol surrounding the thick and thin filaments is very low, about 10-7 mol/L. At this low calcium concentration, very few of the calciumbinding sites on troponin are occupied, and thus crossbridgeactivity is blocked by tropomyosin. Following an action potential, there is a rapid increase in cytosolic calcium concentration, and calcium binds to troponin, removing the blocking effect of tropomyosin and allowing cross-bridge cycling. The source of the increased cytosolic calcium is the sarcoplasmic reticulum within the muscle fiber.
Time relations between a skeletal-muscle fiber action potential and the resulting shortening and relaxation of the muscle fiber.
Sarcoplasmic Reticulum
The sarcoplasmic reticulum in muscle is homologous to the endoplasmic reticulum found in most cells and forms a series of sleevelike structures around each myofibril, one segment surrounding the A band and another the I band. At the end of each segment there are two enlarged regions, known as lateral sacs that are connected to each other by a series of smaller tubular elements. The lateral sacs store the calcium that is released following membrane excitation.
(a) Diagrammatic representation of the sarcoplasmic reticulum, the transverse tubules, and the myofibrils. (b) Anatomical structure of transverse tubules and sarcoplasmic reticulum in a single skeletal-muscle fiber.
Aseparate tubular structure, the transverse tubule (T tubule), crosses the muscle fiber at the level of each A-I junction, passing between adjacent lateral sacs and eventually joining the plasma membrane. The lumen of the T tubule is continuous with the extracellular fluid surrounding the muscle fiber. The membrane of the T tubule, like the plasma membrane, is able to propagate action potentials. Once initiated in the plasma membrane, an action potential is rapidly conducted over the surface of the fiber and into its interior by way of the T tubules. The action potential in a T tubule adjacent to the lateral sacs activates voltagegated proteins in the T-tubule membrane that are physically or chemically linked to calcium-release channels in the membrane of the lateral sacs. Depolarization of the T tubule by an action potential thus leads to the opening of the calcium channels in the lateral sacs, allowing calcium to diffuse from the calcium-rich lumen of the lateral sacs into the cytosol. The rise in cytosolic calcium concentration is normally enough to turn on all the cross bridges in the fiber.
A contraction continues until calcium is removed from troponin, and this is achieved by lowering the calcium concentration in the cytosol back to its pre-release level. The membranes of the sarcoplasmic reticulum contain primary active-transport proteins, Ca-ATPases, that pump calcium ions from the cytosol back into the lumen of the reticulum. As we just saw, calcium is released from the reticulum upon arrival of an action potential in the T tubule, but the pumping of the released calcium back into the reticulum requires a much longer time. Therefore, the cytosolic calcium concentration remains elevated, and the contraction continues for some time after a single action potential.
Release and uptake of calcium by the sarcoplasmic reticulum during contraction and relaxation of a skeletal-muscle fiber.
Functions of ATP in Skeletal-Muscle Contraction
1. Hydrolysis of ATP by myosin energizes the cross bridges, providing the energy for force generation.
2. Binding of ATP to myosin dissociates cross bridges bound to actin, allowing the bridges to repeat their cycle of activity.
3. Hydrolysis of ATP by the Ca-ATPase in the sarcoplasmic reticulum provides the energy for the active transport of calcium ions into the lateral sacs of the reticulum, lowering cytosolic calcium to pre-release levels, ending the contraction, and allowing the muscle fiber to relax.
To reiterate, just as contraction results from the release of calcium ions stored in the sarcoplasmic reticulum, so contraction ends and relaxation begins as calcium is pumped back into the reticulum. ATP is required to provide the energy for the calcium pump, and this is the third major role of ATP in muscle contraction
Membrane Excitation: The Neuromuscular Junction
We have just seen that an action potential in the plasma membrane of a skeletal-muscle fiber is the signal that triggers contraction. The next question we must ask then is: How are these action potentials initiated? Stimulation of the nerve fibers to a skeletal muscle is the only mechanism by which action potentials are initiated in this type of muscle. As we shall learn, there are additional mechanisms for activating cardiac- and smooth-muscle contraction.
The nerve cells whose axons innervate skeletalmuscle fibers are known as motor neurons (or somatic efferent neurons), and their cell bodies are located in either the brainstem or the spinal cord. The axons of motor neurons are myelinated and are the largestdiameter axons in the body. They are therefore able to propagate action potentials at high velocities, allowing signals from the central nervous system to be transmitted to skeletal-muscle fibers with minimal delay.
Upon reaching a muscle, the axon of a motor neuron divides into many branches, each branch forming a single junction with a muscle fiber. A single motor neuron innervates many muscle fibers, but each muscle fiber is controlled by a branch from only one motor neuron. Amotor neuron plus the muscle fibers it innervates is called a motor unit. The muscle fibers in a single motor unit are located in one muscle, but they are scattered throughout the muscle and are not adjacent to each other. When an action potential occurs in a motor neuron, all the muscle fibers in its motor unit are stimulated to contract.
(a) Single motor unit consisting of one motor neuron and the muscle fibers it innervates. (b) Two motor units and their intermingled fibers in a muscle.
The myelin sheath surrounding the axon of each motor neuron ends near the surface of a muscle fiber, and the axon divides into a number of short processes that lie embedded in grooves on the muscle-fiber surface. The region of the muscle-fiber plasma membrane that lies directly under the terminal portion of the axon has special properties and is known as the motor end plate. The junction of an axon terminal with the motor end plate is known as a neuromuscularjunction.
The axon terminals of a motor neuron contain vesicles similar to the vesicles found at synaptic junctions between two neurons. The vesicles contain the neurotransmitter acetylcholine (ACh). When an action potential in a motor neuron arrives at the axon terminal, it depolarizes the nerve plasma membrane, opening voltage-sensitive calcium channels and allowing calcium ions to diffuse into the axon terminal from the extracellular fluid. This calcium binds to proteins that enable the membranes of acetylcholine-containing vesicles to fuse with the nerve plasma membrane thereby releasing acetylcholine into the extracellular cleft separating the axon terminal and the motor end plate.
ACh diffuses from the axon terminal to the motor end plate where it binds to receptors [of the nicotinic type]. The binding of ACh opens an ion channel in each receptor protein. Both sodium and potassium ions can pass through these channels. Because of the differences in electrochemical gradients across the plasma membrane (Chapter 8), more sodium moves in than potassium out, producing a local depolarization of the motor end plate known as an end-plate potential (EPP). Thus, an EPP is analogous to an EPSP (excitatory postsynaptic potential) at a synapse.
The magnitude of a single EPP is, however, much larger than that of an EPSP because neurotransmitter is released over a larger surface area, binding to many more receptors and hence opening many more ion channels. For this reason, one EPP is normally more than sufficient to depolarize the muscle plasma membrane adjacent to the end-plate membrane, by local current flow, to its threshold potential, initiating an action potential.
Sequence of Events Between a Motor Neuron Action Potential and
Skeletal-Muscle Fiber Contraction
Most neuromuscular junctions are located near the middle of a muscle fiber, and newly generated muscle action potentials propagate from this region in both directions toward the ends of the fiber. To repeat, every action potential in a motor neuron normally produces an action potential in each muscle fiber in its motor unit. This is quite different from synaptic junctions, where multiple EPSPs must occur, undergoing temporal and spatial summation, in order for threshold to be reached and an action potential elicited in the postsynaptic membrane. A second difference between synaptic and neuromuscular junctions should be noted. At some synaptic junctions, IPSPs (inhibitory postsynaptic potentials) are produced. They hyperpolarize or stabilize the postsynaptic membrane and decrease the probability of its firing an action potential. In contrast, inhibitory potentials do not occur in human skeletal muscle; all neuromuscular junctions are excitatory. In addition to receptors for ACh, the surface of the motor end plate contains the enzyme acetylcholinesterase, which breaks down ACh, just as occurs at ACh-mediated synapses in the nervous system. ACh bound to receptors is in equilibrium with free ACh in the cleft between the nerve and muscle membranes. As the concentration of free ACh falls because of its breakdown by acetylcholinesterase, less ACh is available to bind to the receptors. When the receptors no longer contain bound ACh, the ion channels in the end plateclose. The depolarized end plate returns to its resting potential and can respond to the subsequent arrival of ACh released by another nerve action potential. There are many ways by which events at the neuromuscular junction can be modified by disease or drugs. For example, the deadly South American arrowhead poison curare binds strongly to the ACh receptors, but it does not open their ion channels and is not destroyed by acetylcholinesterase. When a receptor is occupied by curare, ACh cannot bind to the receptor. Therefore, although the motor nerves still conduct normal action potentials and release ACh, there is no resulting EPP in the motor end plate and hence no contraction. Since the skeletal muscles responsible for breathing, like all skeletal muscles, depend upon neuromuscular transmission to initiate their contraction, curare poisoning can lead to death by asphyxiation.
Drugs similar to curare are used in small amounts to prevent muscular contractions during certain types of surgical procedures when it is necessary to immobilize the surgical field. Patients are artificially ventilated in order to maintain respiration until the drug has been removed from the system.
Neuromuscular transmission can also be blocked by inhibiting acetylcholinesterase. Some organophosphates, which are the main ingredients in certain pesticides and “nerve gases” (the latter developed for biological warfare), inhibit this enzyme. In the presence of such agents, ACh is released normally upon the arrival of an action potential at the axon terminal and binds to the end-plate receptors. The ACh is not destroyed, however, because the acetylcholinesterase is inhibited. The ion channels in the end plate therefore remain open, producing a maintained depolarization of the end plate and the muscle plasma membrane adjacent to the end plate. A skeletal-muscle membrane maintained in a depolarized state cannot generate action potentials because the voltage-gated sodium channels in the membrane have entered an inactive state, which requires repolarization to remove. Thus, the muscle does not contract in response to subsequent nerve stimulation, and the result is skeletal-muscle paralysis and death from asphyxiation. A third group of substances, including the toxin produced by the bacterium Clostridium botulinum, blocks the release of acetylcholine from nerve terminals. Botulinum toxin is an enzyme that breaks down a protein required for the binding and fusion of ACh vesicles with the plasma membrane of the axon terminal.
This toxin, which produces the food poisoning called botulism, is one of the most potent poisons known because of the very small amount necessary to produce an effect.
Mechanics of Single-FiberContraction
The force exerted on an object by a contracting muscle is known as muscle tension, and the force exerted on the muscle by an object (usually its weight) is the load. Muscle tension and load are opposing forces. Whether or not force generation leads to fiber shortening depends on the relative magnitudes of the tension and the load. In order for muscle fibers to shorten, and thereby move a load, muscle tension must be greater than the opposing load. When a muscle develops tension but does not shorten (or lengthen), the contraction is said to be isometric (constant length). Such contractions occur when the muscle supports a load in a constant position or attempts to move an otherwise supported load that is greater than the tension developed by the muscle.
A contraction in which the muscle shortens, while the load on the muscle remains constant, is said to be isotonic (constant tension). A third type of contraction is a lengthening contraction (eccentric contraction). This occurs when an unsupported load on a muscle is greater than the tension being generated by the cross bridges. In this situation, the load pulls the muscle to a longer length in spite of the opposing force being produced by the cross bridges. Such lengthening contractions occur when an object being supported by muscle contraction is lowered, such as occurs when you sit down from a standing position or walk down a flight of stairs. It must be emphasized that in these situations the lengthening of muscle fibers is not an active process produced by the contractile proteins, but a consequence of the external forces being applied to the muscle. In the absence of external lengthening forces, a fiber will only shorten when stimulated; it will never lengthen. All three types of contractions—isometric, isotonic, and lengthening— occur in the natural course of everyday activities. During each type of contraction the cross bridges repeatedly go through the four steps of the cross-bridge cycle. During step 2 of an isotonic contraction, the cross bridges bound to actin move to their angled positions, causing shortening of the sarcomeres. In contrast, during an isometric contraction, the bound cross bridges are unable to move the thin filaments because of the load on the muscle fiber, but they do exert a force on the thin filaments— isometric tension. During a lengthening contraction, the cross bridges in step 2 are pulled backward toward the Z lines by the load while still bound to actin and exerting force. The events of steps 1, 3, and 4 are the same in all three types of contractions. Thus, the chemical changes in the contractile proteins during each type of contraction are the same. The end result (shortening, no length change, or lengthening) is determined by the magnitude of the load on the muscle.
Contraction terminology applies to both single fibers and whole muscles. We first describe the mechanics of single-fiber contractions and later discuss the factors controlling the mechanics of whole-musclecontraction.
Twitch Contractions
The mechanical response of a single muscle fiber to a single action potential is known as a twitch. Following the action potential, there is an interval of a few milliseconds, known as the latent period, before the tension in the muscle fiber begins to increase. During this latent period, the processes associated with excitation-contraction coupling are occurring. The time interval from the beginning of tension development at the end of the latent period to the peak tension is the contraction time. Not all skeletal-muscle fibers have the same twitch contraction time. Some fast fibers have contraction times as short as 10 ms, whereas slower fibers may take 100 ms or longer.
The duration of the contraction time depends on the time that cytosolic calcium remains elevated so that cross bridges can continue to cycle. It is most closely related to the Ca- ATPase activity in the sarcoplasmic reticulum; activity is greater in fast-twitch fibers and less in slow-twitch fibers.
Comparing isotonic and isometric twitches in the same muscle fiber, the latent period in an isotonic twitch is longer than that in an isometric contraction, while the duration of the mechanical event—shortening—is briefer in an isotonic twitch than the duration of force generation in an isometric twitch.
Moreover, the characteristics of an isotonic twitch depend upon the magnitude of the load being lifted: (1) at heavier loads, the latent period is longer, and (2) the velocity of shortening (distance shortened per unit of time), the duration of the twitch, and the distance shortened are all slower or shorter.
Let us look more closely at the sequence of events in an isotonic twitch. Following excitation, the cross bridges begin to develop force, but shortening does not begin until the muscle tension just exceeds the load on the fiber. Thus, before shortening, there is a period of isometric contraction during which the tension increases.
The heavier the load, the longer it takes for the tension to increase to the value of the load, when shortening will begin. If the load on a fiber is increased, eventually a load is reached that the muscle is unable to lift, the velocity and distance of shortening will be zero, and the contraction will become completely isometric.
Load-Velocity Relation
It is a common experience that light objects can be moved faster than heavy objects. That is, the velocity at which a muscle fiber shortens decreases with increasing loads. The shortening velocity is maximal when there is no load and is zero when the load is equal to the maximal isometric tension. At loads greater than the maximal isometric tension, the fiber will lengthen at a velocity that increases with load, and at very high loads the fiber will break. The shortening velocity is determined by the rate at which individual cross bridges undergo their cyclical activity. Because one ATP is split during each crossbridge cycle, the rate of ATP splitting determines the shortening velocity. Increasing the load on a bridge, for complex reasons, decreases the rate of ATP hydrolysis and thus the velocity of shortening.
Frequency-Tension Relation
Since a single action potential in a skeletal-muscle fiber lasts 1 to 2 ms but the twitch may last for 100 ms, it is possible for a second action potential to be initiated during the period of mechanical activity.
Velocity of skeletal-muscle fiber shortening and lengthening as a function of load. Note that the force on the cross bridges during a lengthening contraction is greater than the maximum isometric tension.
The isometric twitch following the first stimulus S1 lasts 150 ms. The second stimulus S2, applied to the muscle fiber 200 ms after S1 when the fiber has completely relaxed, causes a second identical twitch, and a third stimulus S3, equally timed, produces a third identical twitch. The interval between S1 and S2 remains 200 ms, but a third stimulus is applied 60 ms after S2, when the mechanical response resulting from S2 is beginning to decrease but has not yet ended. Stimulus S3 induces a contractile response whose peak tension is greater than that produced by S2. The interval between S2 and S3 is further reduced to 10 ms, and the resulting peak tension is even greater. Indeed, the mechanical response to S3 is a smooth continuation of the mechanical response already induced by S2. The increase in muscle tension from successive action potentials occurring during the phase of mechanical activity is known as summation. A maintained contraction in response to repetitive stimulation is known as a tetanus (tetanic contraction). At low stimulation frequencies, the tension may oscillate as the muscle fiber partially relaxes between stimuli, producing an unfused tetanus. A fused tetanus, with no oscillations, is produced at higher stimulation frequencies.
As the frequency of action potentials increases, the level of tension increases by summation until a maximal fused tetanic tension is reached, beyond which tensioo longer increases with further increases in stimulation frequency. This maximal tetanic tension is about three to five times greater than the isometric twitch tension. Since different muscle fibers have different contraction times, the stimulus frequency that will produce a maximal tetanic tension differs from fiber to fiber.
Summation can be explained by events occurring in the muscle fiber. The explanation requires one new piece of information: A muscle contains passive elastic elements (portions of the thick and thin filaments and tendons) that are in series with the contractile (force-generating) elements. These series elastic elements act like springs through which the active force generated by the cross bridges must pass to be applied to the load. Therefore, the time course of the rise in tension during an isometric contraction includes the time required to stretch the series elastic elements.
The tension produced by a muscle fiber at any instant depends upon (1) the number of cross bridges bound to actin and undergoing step 2 of the crossbridge cycle in each sarcomere, (2) the force produced by each cross bridge and, (3) the amount of time the cross bridges remain active. A single action potential in a skeletal-muscle fiber releases enough calcium to saturate troponin, and all the myosin-binding sites on the thin filaments are therefore initially available. But the binding of energized cross bridges to these sites (step 1 of the cross-bridge cycle) takes time and, as noted above, the stretching of the series elastic elements by the cross bridges also takes time. For these reasons, even though all the binding sites are available initially during a single twitch, maximal tension is not developed instantaneously. Moreover, almost immediately after the release of calcium, it begins to be pumped back into the sarcoplasmic reticulum, and the calcium concentration begins to fall from its initial high value, causing more and more of the myosin-binding sites on actin to become unavailable for cross-bridge binding. Thus, during a single twitch, the cross bridges do not remain active long enough for the series elastic element to be stretched to the maximal tension the cross bridge can exert.
In contrast, during a tetanic contraction, the successive action potentials each release calcium from the sarcoplasmic reticulum before all the calcium from the previous action potential has been pumped back into the reticulum. This results in a maintained elevated cytosolic calcium concentration and prevents a decline in the number of available binding sites on the thin filaments.
Under these conditions, the maximum number of binding sites remains available and the maintained cross-bridge cycling has time to stretch the series elastic elements, thereby transmitting maximal tension to the ends of the fiber.
Length-Tension Relation
The springlike characteristics of the protein titin, which is attached to the Z line at one end and the thick filaments at the other, as described earlier, is responsible for most of the passive elastic properties of relaxed muscles. With increased stretch, the passive tension in a relaxed fiber increases, not from active cross-bridge movements but from elongation of the titin filaments. If the stretched fiber is released, its length will return to an equilibrium length, much like releasing a stretched rubber band. The critical point for this section is that, on top of this increased passive tension due to stretching, the amount of active tension developed by a muscle fiber during contraction, and thus its strength, can be altered by changing the length of the fiber before contraction. One can stretch a muscle fiber to various lengths and measure the magnitude of the active tension generated in response to stimulation at each length. The length at which the fiber develops the greatest isometric active tension is termed the optimal length, lo.
When a muscle fiber length is 60 percent of lo, the fiber develops no tension when stimulated. As length is increased from this point, the isometric tension at each length is increased up to a maximum at lo. Further lengthening leads to a drop in tension. At lengths of 175 percent lo or beyond, the fiber develops no tension when stimulated. When all the skeletal muscles in the body are relaxed, the lengths of most fibers are near lo and thus near the optimal lengths for force generation. The length of a relaxed fiber can be altered by the load on the muscle or the contraction of other muscles that stretch the relaxed fibers, but the extent to which the relaxed length can be changed is limited by the muscle’s attachments to bones. It rarely exceeds a 30 percent change from lo and is often much less. Over this range of lengths, the ability to develop tensioever falls below about half of the tension that can be developed at lo.
The relationship between fiber length and the fiber’s capacity to develop active tension during contraction can be partially explained in terms of the sliding-filament mechanism. Stretching a relaxed muscle fiber pulls the thin filaments past the thick filaments, changing the amount of overlap between them. Stretching a fiber to 1.75 lo pulls the filaments apart to the point where there is no overlap. At this point there can be no cross-bridge binding to actin and no developmentof tension. Between 1.75 lo and lo, more and more filaments overlap, and the tension developed upon stimulation increases in proportion to the increased number of cross bridges in the overlap region.Filament overlap is greatest at lo, allowing the maximal number of cross bridges to bind to the thin filaments, thereby producing maximal tension. The tension decline at lengths less than lo is the result of several factors. For example, (1) the overlapping sets of thin filaments from opposite ends of the sarcomere may interfere with the cross bridges’ ability to bind and exert force, and (2) for unknown reasons, the affinity of troponin for calcium decreases at short fiber lengths, resulting in fewer accessible sites on the thin filaments for cross-bridge binding.
Skeletal-Muscle Energy Metabolism
As we have seen, ATP performs three functions directly related to muscle-fiber contraction and relaxation. Io other cell type does the rate of ATP breakdown increase so much from one moment to the next as in a skeletal muscle fiber (20 to several hundredfold depending on the type of muscle fiber) when it goes from rest to a state of contractile activity. The small supply of preformed ATP that exists at the start of contractile activity would only support a few twitches. If a fiber is to sustain contractile activity, molecules of ATP must be produced by metabolism as rapidly as they are broken down during the contractile process.
There are three ways a muscle fiber can form ATP during contractile activity: (1) phosphorylation of ADP by creatine phosphate, (2) oxidative phosphorylation of ADP in the mitochondria, and (3) substrate-level phosphorylation of ADP by the glycolyticpathway in the cytosol.
Phosphorylation of ADP by creatine phosphate (CP) provides a very rapid means of forming ATP at the onset of contractile activity. When the chemical bond between creatine (C) and phosphate is broken, the amount of energy released is about the same as that released when the terminal phosphate bond in ATP isbroken. This energy, along with the phosphate group, can be transferred to ADP to form ATP in a reversible reaction catalyzed by creatine kinase:
Although creatine phosphate is a high-energy molecule, its energy cannot be released by myosin to drive cross-bridge activity. During periods of rest, muscle fibers build up a concentration of creatine phosphateapproximately five times that of ATP. At the beginning of contraction, when the concentration of ATP begins to fall and that of ADP to rise owing to the increased rate of ATP breakdown by myosin, mass action favors the formation of ATP from creatine phosphate. This transfer of energy is so rapid that the concentration of ATP in a muscle fiber changes very little at the start of contraction, whereas the concentration of creatine phosphate falls rapidly.
Although the formation of ATP from creatine phosphate is very rapid, requiring only a single enzymatic reaction, the amount of ATP that can be formed by this process is limited by the initial concentration of creatine phosphate in the cell. If contractile activity is to be continued for more than a few seconds, the muscle must be able to form ATP from the other two sources listed above. The use of creatine phosphate at the start of contractile activity provides the few seconds necessary for the slower, multienzyme pathways of oxidative phosphorylation and glycolysis to increase their rates of ATP formation to levels that match the rates of ATP breakdown. At moderate levels of muscular activity, most of the ATP used for muscle contraction is formed by oxidative phosphorylation, and during the first 5 to 10 min of such exercise, muscle glycogen is the major fuel contributing to oxidative phosphorylation. For the next 30 min or so, blood-borne fuels become dominant, blood glucose and fatty acids contributing approximately equally; beyond this period, fatty acids become progressively more important, and glucose utilization decreases.
If the intensity of exercise exceeds about 70 percent of the maximal rate of ATP breakdown, however, glycolysis contributes an increasingly significant fraction of the total ATP generated by the muscle. The glycolytic pathway, although producing only small quantities of ATP from each molecule of glucose metabolized, can produce large quantities of ATP when enough enzymes and substrate are available, and it can do so in the absence of oxygen. The glucose for glycolysis can be obtained from two sources: the blood or the stores of glycogen within the contracting muscle fibers. As the intensity of muscle activity increases, a greater fraction of the total ATP production is formed by anaerobic glycolysis, with a corresponding increase in the production of lactic acid (which dissociates to yield lactate ions and hydrogen ions).
At the end of muscle activity, creatine phosphate and glycogen levels in the muscle have decreased, and to return a muscle fiber to its original state, these energy-storing compounds must be replaced. Both processes require energy, and so a muscle continues to consume increased amounts of oxygen for some time after it has ceased to contract, as evidenced by the fact that one continues to breathe deeply and rapidly for a period of time immediately following intense exercise. This elevated consumption of oxygen following exercise repays what has been called the oxygen debt— that is, the increased production of ATP by oxidative phosphorylation following exercise that is used to restore the energy reserves in the form of creatine phosphate and glycogen.
Muscle Fatigue
When a skeletal-muscle fiber is repeatedly stimulated, the tension developed by the fiber eventually decreaseseven though the stimulation continues. This decline in muscle tension as a result of previous contractile activity is known as muscle fatigue. Additional characteristics of fatigued muscle are a decreased shortening velocity and a slower rate of relaxation. The onset of fatigue and its rate of development depend on the type of skeletal-muscle fiber that is active and on the intensity and duration of contractile activity.
If a muscle is allowed to rest after the onset of fatigue, it can recover its ability to contract upon restimulation. The rate of recovery depends upon the duration and intensity of the previous activity. Some muscle fibers fatigue rapidly if continuously stimulated but also recover rapidly after a briefrest. This is the type of fatigue (high-frequency fatigue) that accompanies high-intensity, short-duration exercise, such as weight lifting. In contrast, low-frequency fatigue develops more slowly with low-intensity, longduration exercise, such as long-distance running, during which there are cyclical periods of contraction and relaxation, and requires much longer periods of rest, often up to 24 h, before the muscle achieves complete recovery.
It might seem logical that depletion of energy in the form of ATP would account for fatigue, but the ATP concentration in fatigued muscle is found to be only slightly lower than in a resting muscle, and not low enough to impair cross-bridge cycling. If contractile activity were to continue without fatigue, the ATP concentration could decrease to the point that the cross bridges would become linked in a rigor configuration, which is very damaging to muscle fibers. Thus, muscle fatigue may have evolved as a mechanism for preventing the onset of rigor.
Multiple factors can contribute to the fatigue of skeletal muscle. Fatigue from high-intensity, shortduration exercise occurs primarily because of a failure of the muscle action potential to be conducted into the fiber along the T tubules and thus a failure to releasecalcium from the sarcoplasmic reticulum. The conduction failure results from the build up of potassiumions in the small volume of the T tubule with each of the initial action potentials, which leads to a partial depolarization of the membrane and eventually failure to produce action potentials in the T-tubular membrane. Recovery is rapid with rest as the accumulated potassium diffuses out of the tubule, restoring excitability. With low-intensity, long-duration exercise a number of processes have been implicated in fatigue, but no single process can completely account for the fatigue from this type of exercise. One of the major factors is the build up of lactic acid. Since the hydrogenion concentration can alter protein conformation and thus protein activity, the acidification of the muscle alters a number of muscle proteins, including actin and myosin, as well as proteins involved in calcium release.
Recovery from this kind of fatigue probably requires protein synthesis to replace those proteins that have been altered by the fatigue process. Finally, although depletion of ATP is not a cause of fatigue, the decrease in muscle glycogen, which is supplying much of the fuel for contraction, correlates closely with fatigue onset.
Another type of fatigue quite different from muscle fatigue is due to failure of the appropriate regions of the cerebral cortex to send excitatory signals to the motor neurons. This is called central command fatigue, and it may cause an individual to stop exercising even though the muscles are not fatigued. An athlete’s performance depends not only on the physical state of the appropriate muscles but also upon the “will to win”—that is, the ability to initiate central commands to muscles during a period of increasingly distressfulsensations.
Types of Skeletal-Muscle Fibers
All skeletal-muscle fibers do not have the same mechanical and metabolic characteristics. Different types of fibers can be identified on the basis of (1) their maximal velocities of shortening—fast and slow fibers— and (2) the major pathway used to form ATP—oxidative and glycolytic fibers. Fast and slow fibers contain myosin isozymes that differ in the maximal rates at which they split ATP, which in turn determine the maximal rate of crossbridge cycling and hence the fibers’ maximal shortening velocity. Fibers containing myosin with high ATPase activity are classified as fast fibers, and those containing myosin with lower ATPase activity are slow fibers. Although the rate of cross-bridge cycling is about four times faster in fast fibers than in slow fibers, the force produced by both types of cross bridges is about the same. The second means of classifying skeletal-muscle fibers is according to the type of enzymatic machinery available for synthesizing ATP. Some fibers contain numerous mitochondria and thus have a high capacity for oxidative phosphorylation. These fibers are classified as oxidative fibers. Most of the ATP produced by such fibers is dependent upon blood flow to deliver oxygen and fuel molecules to the muscle, and these fibers are surrounded by numerous small blood vessels.
They also contain large amounts of an oxygenbinding protein known as myoglobin, which increases the rate of oxygen diffusion within the fiber and provides a small store of oxygen. The large amounts of myoglobin present in oxidative fibers give the fibers a dark-red color, and thus oxidative fibers are often referred to as red muscle fibers.
In contrast, glycolytic fibers have few mitochondria but possess a high concentration of glycolytic enzymes and a large store of glycogen. Corresponding totheir limited use of oxygen, these fibers are surrounded by relatively few blood vessels and contain little myoglobin.
The lack of myoglobin is responsible for the pale color of glycolytic fibers and their designation as white muscle fibers. On the basis of these two characteristics, three types of skeletal-muscle fibers can be distinguished:
1. Slow-oxidative fibers (type I) combine low myosin-ATPase activity with high oxidative capacity.
2. Fast-oxidative fibers (type IIa) combine high myosin-ATPase activity with high oxidative capacity.
3. Fast-glycolytic fibers (type IIb) combine highmyosin-ATPase activity with high glycolyticcapacity.
Note that the fourth theoretical possibility—slowglycolytic fibers—is not found.
In addition to these biochemical differences, there are also size differences, glycolytic fibers generally having much larger diameters than oxidative fibers. This fact has significance for tension development. The number of thick and thin filaments per unit of cross-sectional area is about the same in all types of skeletal-muscle fibers. Therefore, the larger the diameter of a muscle fiber, the greater the total number of thick and thin filaments acting in parallel to produce force, and the greater the maximum tension it can develop (greater strength).
Characteristics of the Three Types of Skeletal-Muscle Fibers
Accordingly, the average glycolytic fiber, with its larger diameter, develops more tension when it contracts than does an average oxidative fiber.
These three types of fibers also differ in their capacity to resist fatigue. Fast-glycolytic fibers fatigue rapidly, whereas slow-oxidative fibers are very resistant to fatigue, which allows them to maintain contractile activity for long periods with little loss of tension. Fast-oxidative fibers have an intermediate capacity to resist fatigue.
Whole-Muscle Contraction
As described earlier, whole muscles are made up of many muscle fibers organized into motor units. All the muscle fibers in a single motor unit are of the same fiber type. Thus, one can apply the fiber type designation to the motor unit and refer to slow-oxidative motor units, fast-oxidative motor units, and fastglycolytic motor units.
Most muscles are composed of all three motor unit types interspersed with each other. No muscle has only a single fiber type.
Depending on the proportions of the fiber types present, muscles can differ considerably in their maximal contraction speed, strength, and fatigability. For example, the muscles of the back and legs, which must be able to maintain their activity for long periods of time without fatigue while supporting an upright posture, contain large numbersof slow-oxidative and fast-oxidative fibers. In contrast, the muscles in the arms may be called upon to produce large amounts of tension over a short time period, as when lifting a heavy object, and these muscles have a greater proportion of fast-glycolytic fibers.
We will now use the characteristics of single fibers to describe whole-muscle contraction and its control. Control of Muscle Tension The total tension a muscle can develop depends upon two factors: (1) the amount of tension developed by each fiber, and (2) the number of fibers contracting at any time. By controlling these two factors, the nervous system controls whole-muscle tension, as well as amount of tension developed in a single fiber. The number of fibers contracting at any time depends on: (1) the number of fibers in each motor unit (motor unit size), and (2) the number of active motor units.
Motor unit size varies considerably from one muscle to another. The muscles in the hand and eye, which produce very delicate movements, contain small motor units. For example, one motor neuron innervates only about 13 fibers in an eye muscle. In contrast, in the more coarsely controlled muscles of the back and legs, each motor unit is large, containing hundreds and in some cases several thousand fibers. When a muscle is composed of small motor units, the total tension produced by the muscle can be increased in small steps by activating additional motor units. If the motor units are large, large increases in tension will occur as each additional motor unit is activated. Thus, finer control of muscle tension is possible in muscles with small motor units.
The force produced by a single fiber, as we have seen earlier, depends in part on the fiber diameter— the greater the diameter, the greater the force. We have also noted that fast-glycolytic fibers have the largest diameters. Thus, a motor unit composed of 100 fastglycolytic fibers produces more force that a motor unit composed of 100 slow-oxidative fibers. In addition, fast-glycolytic motor units tend to have more muscle fibers. For both of these reasons, activating a fastglycolytic motor unit will produce more force than activating a slow-oxidative motor unit. The process of increasing the number of motor units that are active in a muscle at any given time is called recruitment. It is achieved by increasing the excitatory synaptic input to the motor neurons. The greater the number of active motor neurons, the more motor units recruited, and the greater the muscle tension. Motor neuron size plays an important role in the recruitment of motor units (the size of a motor neuron refers to the diameter of the nerve cell body, which is usually correlated with the diameter of its axon, and does not refer to the size of the motor unit the neuron controls). Given the same number of sodium ions entering a cell at a single excitatory synapse in a large and in a small motor neuron, the small neuron will undergo a greater depolarization because these ions will be distributed over a smaller membrane surface area. Accordingly, given the same level of synaptic input, the smallest neurons will be recruited first—that is, will begin to generate action potentials first. The larger neurons will be recruited only as the level of synaptic input increases. Since the smallest motor neurons innervate the slow-oxidative motor units, these motor units are recruited first, followed by fastoxidative motor units, and finally, during very strong contractions, by fast-glycolytic motor units.
Thus, during moderate-strength contractions, such as are used in most endurance types of exercise, relativelyfew fast-glycolytic motor units are recruited, and most of the activity occurs in oxidative fibers, which are more resistant to fatigue. The large fast-glycolytic motor units, which fatigue rapidly, begin to be recruited when the intensity of contraction exceeds about 40 percent of the maximal tension that can be produced by the muscle. In conclusion, the neural control of whole-muscle tension involves both the frequency of action potentials in individual motor units (to vary the tension generatedby the fibers in that unit) and the recruitment of motor units (to vary the number of active fibers). Most motor neuron activity occurs in bursts of action potentials, which produce tetanic contractions of individual motor units rather than single twitches. Recall that the tension of a single fiber increases only threeto fivefold when going from a twitch to a maximal tetanic contraction. Therefore, varying the frequency of action potentials in the neurons supplying them provides a way to make only three- to fivefold adjustments in the tension of the recruited motor units. The force a whole muscle exerts can be varied over a much wider range than this, from very delicate movements to extremely powerful contractions, by the recruitment of motor units. Thus recruitment provides the primary means of varying tension in a whole muscle. Recruitment is controlled by the central commands from the motor centers in the brain to the various motor neurons.
Control of Shortening Velocity
As we saw earlier, the velocity at which a single muscle fiber shortens is determined by (1) the load on thefiber and (2) whether the fiber is a fast fiber or a slow fiber. Translated to a whole muscle, these characteristics become (1) the load on the whole muscle and (2) the types of motor units in the muscle. For the whole muscle, however, recruitment becomes a third very important factor, one that explains how the shortening velocity can be varied from very fast to very slow even though the load on the muscle remains constant.
Consider, for the sake of illustration, a muscle composed of only two motor units of the same size and fiber type. One motor unit by itself will lift a 4-g load more slowly than a 2-g load because the shortening velocity decreases with increasing load. When both units are active and a 4-g load is lifted, each motor unit bears only half the load, and its fibers will shorten as if it were lifting only a 2-g load. In other words, the muscle will lift the 4-g load at a higher velocity when both motor units are active. Thus recruitment of motor units leads to an increase in both force and velocity.
Muscle Adaptation to Exercise
The regularity with which a muscle is used, as well as the duration and intensity of its activity, affects the properties of the muscle. If the neurons to a skeletal muscle are destroyed or the neuromuscular junctions become nonfunctional, the denervated muscle fibers will become progressively smaller in diameter, and the amount of contractile proteins they contain will decrease. This condition is known as denervation atrophy. A muscle can also atrophy with its nerve supply intact if the muscle is not used for a long period of time, as when a broken arm or leg is immobilized in a cast. This condition is known as disuse atrophy. In contrast to the decrease in muscle mass that results from a lack of neural stimulation, increased amounts of contractile activity—in other words, exercise— can produce an increase in the size (hypertrophy) of muscle fibers as well as changes in their capacity for ATP production.
Since the number of fibers in a muscle remains essentially constant throughout adult life, the changes in muscle size with atrophy and hypertrophy do not result from changes in the number of muscle fibers butin the metabolic capacity and size of each fiber. Exercise that is of relatively low intensity but of long duration (popularly called “aerobic exercise”), such as running and swimming, produces increases inthe number of mitochondria in the fibers that are recruited in this type of activity. In addition, there is an increase in the number of capillaries around these fibers. All these changes lead to an increase in the capacity for endurance activity with a minimum of fatigue.
(Surprisingly, fiber diameter decreases slightly, and thus there is a small decrease in the maximal strength of muscles as a result of endurance exercise.) As we shall see in later chapters, endurance exercise produces changes not only in the skeletal musclesbut also in the respiratory and circulatory systems,changes that improve the delivery of oxygen and fuelmolecules to the muscle.
In contrast, short-duration, high-intensity exercise (popularly called “strength training”), such as weight lifting, affects primarily the fast-glycolytic fibers, which are recruited during strong contractions. These fibers undergo an increase in fiber diameter (hypertrophy) due to the increased synthesis of actin andmyosin filaments, which form more myofibrils. In addition, the glycolytic activity is increased by increasingthe synthesis of glycolytic enzymes. The result ofsuch high-intensity exercise is an increase in the strength of the muscle and the bulging muscles of a conditioned weight lifter. Such muscles, although very powerful, have little capacity for endurance, and they fatigue rapidly.
Exercise produces little change in the types of myosin enzymes formed by the fibers and thus little change in the proportions of fast and slow fibers in a muscle. As described above, however, exercise does change the rates at which metabolic enzymes are synthesized,leading to changes in the proportion of oxidative and glycolytic fibers within a muscle. With endurance training, there is a decrease in the number of fast-glycolytic fibers and an increase in the number of fast-oxidative fibers as the oxidative capacity of the fibers is increased. The reverse occurs with strength training as fast-oxidative fibers are converted to fastglycolyticfibers.
The signals responsible for all these changes in muscle with different types of activity are unknown.They are related to the frequency and intensity of the contractile activity in the muscle fibers and thus to the pattern of action potentials produced in the muscleover an extended period of time.
Because different types of exercise produce quite different changes in the strength and endurance capacity of a muscle, an individual performing regular exercises to improve muscle performance mustchoose a type of exercise that is compatible with the type of activity he or she ultimately wishes to perform.
Thus, lifting weights will not improve the endurance of a long-distance runner, and jogging will not produce the increased strength desired by a weight lifter. Most exercises, however, produce some effects on both strength and endurance. These changes in muscle in response to repeatedperiods of exercise occur slowly over a period of weeks. If regular exercise is stopped, the changes in the muscle that occurred as a result of the exercise will slowly revert to their unexercised state.The maximum force generated by a muscle decreases by 30 to 40 percent between the ages of 30 and 80. This decrease in tension-generating capacity is due primarily to a decrease in average fiber diameter. Some of the change is simply the result of diminishing physical activity with age and can be prevented by exercise programs. The ability of a muscle to adapt to exercise, however, decreases with age: The same intensity and duration of exercise in an older individual will not produce the same amount of change as in a younger person. This decreased ability to adapt toincreased activity is seen in most organs as one ages.
This effect of aging, however, is only partial, and there is no question that even in the elderly, exercisecan produce significant adaptation. Aerobic traininghas received major attention because of its effect on thecardiovascular system. Strength training of a modest degree, however, is also strongly recommended because it can partially prevent the loss of muscle tissue that occurs with aging. Moreover, it helps maintain stronger bones.
Extensive exercise by an individual whose muscles have not been used in performing that particulartype of exercise leads to muscle soreness the next day.This soreness is the result of a mild inflammation in the muscle, which occurs whenever tissues are damaged. The most severe inflammation occurs following a period of lengthening contractions, indicating that the lengthening of a muscle fiber by an external force produces greater muscle damage than do either isotonic or isometric contractions. Thus, exercising by gradually lowering weights will produce greater muscle soreness than an equivalent amount of weight lifting.
Lever Action of Muscles and Bones
A contracting muscle exerts a force on bones through its connecting tendons. When the force is great enough, the bone moves as the muscle shortens. A contracting muscle exerts only a pulling force, so that as the muscle shortens, the bones to which it is attached are pulled toward each other. Flexion refers to the bending of a limb at a joint, whereas extension is the straightening of a limb. These opposing motions require at least two muscles, one to cause flexion and the other extension. Groups of muscles that produce oppositely directed movements at a joint are known as antagonists. For example, it can be seen that contraction of the biceps causes flexion of thearm at the elbow, whereas contraction of the antagonistic muscle, the triceps, causes the arm to extend. Both muscles exert only a pulling force upon the forearm when they contract. Sets of antagonistic muscles are required not only for flexion-extension, but also for side-to-side movements or rotation of a limb. The contraction of some muscles leads to two types of limb movement, dependingon the contractile state of other muscles acting on the same limb. For example, contraction of the gastrocnemius muscle in the leg causes a flexion of the leg at the knee, as in walking. However, contraction of the gastrocnemius muscle with the simultaneous contraction of the quadriceps femoris (which causes extension of the lower leg) prevents the knee joint from bending, leaving only the ankle joint capable of moving. The foot is extended, and the body rises on tiptoe.
The muscles, bones, and joints in the body are arranged in lever systems. The basic principle of a lever is illustrated by the flexion of the arm by the biceps muscle (Figure 11–33), which exerts an upward pulling force on the forearm about
However, the mechanical disadvantage under which most muscle level systems operate is offset by increased maneuverability. When the biceps shortens
Smooth Muscles
Having described the properties and control of skeletal muscle, we now examine the second of the three types of muscle found in the body—smooth muscle. Two characteristics are common to all smooth muscles: they lack the cross-striated banding pattern found in skeletal and cardiac fibers (hence the name “smooth” muscle), and the nerves to them are derived from the autonomic division of the nervous system rather than the somatic division. Thus, smooth muscle is not normally under direct voluntary control. Smooth muscle, like skeletal muscle, uses crossbridge movements between actin and myosin filaments to generate force, and calcium ions to control cross-bridge activity. However, the organization of the contractile filaments and the process of excitationcontraction coupling are quite different in these two types of muscle. Furthermore, there is considerable diversity among smooth muscles with respect to the mechanism of excitation-contraction coupling.
Structure
Each smooth-muscle fiber is a spindle-shaped cell with a diameter ranging from 2 to 10 _m, as compared to a range of 10 to 100 _m for skeletal-muscle. While skeletal-muscle fibers are multinucleate cells that are unable to divide once they have differentiated, smooth-muscle fibers have a single nucleus and have the capacity to divide throughout the life of an individual. Smooth-muscle cells can be stimulated to divide by a variety of paracrine agents, often in response to tissue injury. Two types of filaments are present in the cytoplasm of smooth-muscle fibers: thick myosin-containing filaments and thin actin-containing filaments. The latter are anchored either to the plasma membrane or to cytoplasmic structures known as dense bodies, which are functionally similar to the Z lines in skeletal-muscle fibers. Note that the filaments are oriented slightly diagonally to the long axis of the cell. When the fiber shortens, the regions of the plasma membrane between the points where actin is attached to the membrane balloon out. The thick and thin filaments are not organized into myofibrils, as in striated muscles, and there is no regular alignment of these filaments into sarcomeres, which accounts for the absence of a banding pattern. Nevertheless, smooth-muscle contraction occurs by a sliding-filament mechanism. The concentration of myosin in smooth muscle is only about one-third of that in striated muscle, whereas the actin content can be twice as great. In spite of these differences, the maximal tension per unit of cross-sectional area developed by smooth muscles is similar to that developed by skeletal muscle.
The isometric tension produced by smoothmuscle fibers varies with fiber length in a manner qualitatively similar to that observed in skeletal muscle. There is an optimal length at which tension development is maximal, and less tension is generated at lengths shorter or longer than this optimal length. The range of muscle lengths over which smooth muscle is able to develop tension is greater, however, than it is in skeletal muscle. This property is highly adaptive since most smooth muscles surround hollow organs that undergo changes in volume with accompanying changes in the lengths of the smooth-muscle fibers in their walls. Even with relatively large increases in volume, as during the accumulation of large amounts of urine in the bladder, the smooth-muscle fibers in the wall retain some ability to develop tension, whereas such distortion might stretch skeletalmuscle fibers beyond the point of thick- and thinfilament overlap.
Membrane Activation
In contrast to skeletal muscle, in which membrane activationis dependent on a single input—the somatic neurons to the muscle—many inputs to a smoothmuscle plasma membrane can alter the contractile activity of the muscle. Some of these increase contraction while others inhibit it. Moreover, at any one time, multiple inputs may be occurring, with the contractile state of the muscle dependent on the relative intensity of the various inhibitory and excitatory stimuli. All these inputs influence contractile activity by altering cytosolic calcium concentration as described in the previous section.
Some smooth muscles contract in response to membrane depolarization including action potentials, whereas others can contract in the absence of any membrane potential change. Interestingly, in smooth muscles in which action potentials occur, calcium ions, rather than sodium ions, carry positive charge into the cell during the rising phase of the action potential— that is, depolarization of the membrane opens voltagegated calcium channels, producing calcium-mediated action potentials rather than sodium-mediated ones.
Another very important point needs to be made about electrical activity and cytosolic calcium concentration in smooth muscle. Unlike the situation in striated muscle, in smooth muscle cytosolic calcium concentration can be increased (or decreased) by graded depolarizations (or hyperpolarizations) in membrane potential, which increase or decrease the number of open calcium channels.
Spontaneous Electrical Activity Some types of smooth-muscle fibers generate action potentials spontaneously in the absence of any neural or hormonal input. The plasma membranes of such fibers do not maintain a constant resting potential. Instead, they gradually depolarize until they reach the threshold potential and produce an action potential. Following repolarization, the membrane again begins to depolarize, so that a sequence of action potentials occurs, producing a tonic state of contractile activity. The potential change occurring during the spontaneous depolarization to threshold is known as a pacemaker potential. (As described in other chapters, some cardiac-muscle fibers and a few neurons in the central nervous system also have pacemaker potentials and can spontaneously generate action potentials in the absence of external stimuli.)
Nerves and Hormones The contractile activity of smooth muscles is influenced by neurotransmitters released by autonomic nerve endings. Unlike skeletalmuscle fibers, smooth-muscle fibers do not have a specialized motor end-plate region. As the axon of a postganglionic autonomic neuron enters the region of smooth-muscle fibers, it divides into numerous branches, each branch containing a series of swollen regions known as varicosities. Each varicosity contains numerous vesicles filled with neurotransmitter, some of which are released when an action potential passes the varicosity. Varicosities from a single axon may be located along several muscle fibers, and a single muscle fiber may be located near varicosities belonging to postganglionic fibers of both sympathetic and parasympathetic neurons.
Local Factors Local factors, including paracrine agents, acidity, oxygen concentration, osmolarity, and the ion composition of the extracellular fluid, can also alter smooth-muscle tension. Responses to local factors provide a means for altering smooth-muscle contraction in response to changes in the muscle’s immediate internal environment, which can lead to regulation that is independent of long-distance signals from nerves and hormones.
Some smooth muscles respond by contracting when they are stretched. Stretching opens mechanosensitive ion channels, leading to membrane depolarization.
The resulting contraction opposes the forces acting to stretch the muscle. On the other hand, some local factors induce smooth-muscle relaxation. Nitric oxide (NO) is one of the most commonly encountered paracrine agents that produces smooth-muscle relaxation. NO is released from some nerve terminals as well as a variety of epithelial and endothelial cells. Because of the short life span of this reactive molecule, it acts as a paracrine agent, influencing only those cells that are very near its release site.
Single-Unit Smooth Muscle The muscle fibers in a single-unit smooth muscle undergo synchronous activity, both electrical and mechanical; that is, the whole muscle responds to stimulation as a single unit. This occurs because each muscle fiber is linked to adjacent fibers by gap junctions, through which action potentials occurring in one cell are propagated to other cells by local currents. Therefore, electrical activity occurring anywhere within a group of single-unit smoothmuscle fibers can be conducted to all the other connected cells.
Characteristics of Muscle Fibers
Cardiac Action Potentials and
Excitation of the SA Node
A typical ventricular myocardial cell action potential is illustrated in Figure 14–18a. The plasma-membrane permeability changes that underlie it are shown in Figure As in skeletal-muscle cells and neurons, the resting membrane is much more permeable to potassium than to sodium. Therefore, the resting membrane potential is much closer to the potassium equilibrium potential (_90 mV) than to the sodium equilibrium potential (_60 mV). Similarly, the depolarizing phase of the action potential is due mainly to a positivefeedback increase in sodium permeability caused by the opening of voltage-gated sodium channels; that is, the channels are opened by depolarization. At almost the same time, the permeability to potassium decreases as certain potassium channels close, and this also contributes to the membrane depolarization. Again as in skeletal-muscle cells and neurons, the increased sodium permeability is very transient, since the sodium channels quickly close again. Unlike the case in these other excitable tissues, however, in cardiac muscle the return of sodium permeability toward its resting value is not accompanied by membrane repolarization. The membrane remains depolarized at a plateau of about 0 mV (Figure 14–18a). The reasons for this continued depolarization are (1) potassium permeability stays below the resting value (that is, the potassium channels mentioned above remain closed), and (2) there is a marked increase in the membrane permeability to calcium. The second reason is the more important of the two, and the explanation for it is as follows.
In myocardial cells, the original membrane depolarization causes voltage-gated calcium channels in the plasma membrane to open, which results in a flow of calcium ions down their electrochemical gradient into the cell. These channels are referred to as slow channels because there is a delay in their opening.
The flow of positive calcium ions into the cell just balances the flow of positive potassium charge out of the cell and keeps the membrane depolarized at the plateau value. Ultimately, repolarization does occur when the permeabilities of calcium and potassium return to their original state.
The action potentials of atrial cells, except those of the SA node, are similar in shape to those just described for ventricular cells, although the duration of their plateau phase is shorter. In contrast, there are extremely important differences between action potentials of the vast majority of the atrial and ventricular myocardial cells, as just described, and those in the conducting system. Figure illustrates the action potentials of a myocardial cell from the SA node. Note that the resting potential of the SA-node cell is not steady but instead manifests a slow depolarization. This gradual depolarization is known as a pacemaker potential; it brings the membrane potential to threshold, at which point an action potential occurs. Following the peak of the action potential, the membrane repolarizes, and the gradual depolarization begins again.
Thus, the pacemaker potential provides the SA node with automaticity, the capacity for spontaneous, rhythmical self-excitation. The slope of the pacemaker potential—that is, how quickly the membrane potential changes per unit time—determines how quickly threshold is reached and the next action potential elicited. The inherent rate of the SA node—the rate exhibited in the total absence of any neural or hormonal input to the node—is approximately 100 depolarizations per minute.
The spinal cord is the most important structure between the body and the brain. The spinal cord extends from the foramen magnum where it is continuous with the medulla to the level of the first or second lumbar vertebrae. It is a vital link between the brain and the body, and from the body to the brain. The spinal cord is 40 to 50 cm long and 1 cm to 1.5 cm in diameter. Two consecutive rows of nerve roots emerge on each of its sides. These nerve roots join distally to form 31 pairs of spinal nerves. The spinal cord is a cylindrical structure of nervous tissue composed of white and gray matter, is uniformly organized and is divided into four regions: cervical (C), thoracic (T), lumbar (L) and sacral (S), each of which is comprised of several segments. The spinal nerve contains motor and sensory nerve fibers to and from all parts of the body. Each spinal cord segment innervates a dermatome.
General Features
1. Similar cross-sectional structures at all spinal cord levels.
2. It carries sensory information (sensations) from the body and some from the head to the central nervous system (CNS) via afferent fibers, and it performs the initial processing of this information.
3. Motor neurons in the ventral horn project their axons into the periphery to innervate skeletal and smooth muscles that mediate voluntary and involuntary reflexes.
4. It contains neurons whose descending axons mediate autonomic control for most of the visceral functions.
5. It is of great clinical importance because it is a major site of traumatic injury and the locus for many disease processes.
Although the spinal cord constitutes only about 2% of the central nervous system (CNS), its functions are vital. Knowledge of spinal cord functional anatomy makes it possible to diagnose the nature and location of cord damage and many cord diseases.
The spinal cord is divided into four different regions: the cervical, thoracic, lumbar and sacral regions. The different cord regions can be visually distinguished from one another. Two enlargements of the spinal cord can be visualized: The cervical enlargement, which extends between C3 to T1; and the lumbar enlargements which extends between L1 to S2.
The cord is segmentally organized. There are 31 segments, defined by 31 pairs of nerves exiting the cord. These nerves are divided into 8 cervical, 12 thoracic, 5 lumbar, 5 sacral, and 1 coccygeal nerve (Figure 3.2). Dorsal and ventral roots enter and leave the vertebral column respectively through intervertebral foramen at the vertebral segments corresponding to the spinal segment.
The cord is sheathed in the same three meninges as is the brain: the pia, arachnoid and dura. The dura is the tough outer sheath, the arachnoid lies beneath it, and the pia closely adheres to the surface of the cord (Figure 3.3). The spinal cord is attached to the dura by a series of lateral denticulate ligaments emanating from the pial folds.
During the initial third month of embryonic development, the spinal cord extends the entire length of the vertebral canal and both grow at about the same rate. As development continues, the body and the vertebral column continue to grow at a much greater rate than the spinal cord proper. This results in displacement of the lower parts of the spinal cord with relation to the vertebrae column. The outcome of this uneven growth is that the adult spinal cord extends to the level of the first or second lumbar vertebrae, and the nerves grow to exit through the same intervertebral foramina as they did during embryonic development. This growth of the nerve roots occurring within the vertebral canal, results in the lumbar, sacral, and coccygeal roots extending to their appropriate vertebral levels.
All spinal nerves, except the first, exit below their corresponding vertebrae. In the cervical segments, there are 7 cervical vertebrae and 8 cervical nerves (Figure 3.2). C1-C7 nerves exit above their vertebrae whereas the C8 nerve exits below the C7 vertebra. It leaves between the C7 vertebra and the first thoracic vertebra. Therefore, each subsequent nerve leaves the cord below the corresponding vertebra. In the thoracic and upper lumbar regions, the difference between the vertebrae and cord level is three segments. Therefore, the root filaments of spinal cord segments have to travel longer distances to reach the corresponding intervertebral foramen from which the spinal nerves emerge. The lumbosacral roots are known as the cauda equina.
Each spinal nerve is composed of nerve fibers that are related to the region of the muscles and skin that develops from one body somite (segment). A spinal segment is defined by dorsal roots entering and ventral roots exiting the cord, (i.e., a spinal cord section that gives rise to one spinal nerve is considered as a segment.)
A dermatome is an area of skin supplied by peripheral nerve fibers originating from a single dorsal root ganglion. If a nerve is cut, one loses sensation from that dermatome. Because each segment of the cord innervates a different region of the body, dermatomes can be precisely mapped on the body surface, and loss of sensation in a dermatome can indicate the exact level of spinal cord damage in clinical assessment of injury. It is important to consider that there is some overlap between neighboring dermatomes. Because sensory information from the body is relayed to the CNS through the dorsal roots, the axons originating from dorsal root ganglion cells are classified as primary sensory afferents, and the dorsal root’s neurons are the first order (1°) sensory neuron. Most axons in the ventral roots arise from motor neurons in the ventral horn of the spinal cord and innervate skeletal muscle. Others arise from the lateral horn and synapse on autonomic ganglia that innervate visceral organs. The ventral root axons join with the peripheral processes of the dorsal root ganglion cells to form mixed afferent and efferent spinal nerves, which merge to form peripheral nerves. Knowledge of the segmental innervation of the cutaneous area and the muscles is essential to diagnose the site of an injury.
A transverse section of the adult spinal cord shows white matter in the periphery, gray matter inside, and a tiny central canal filled with CSF at its center. Surrounding the canal is a single layer of cells, the ependymal layer. Surrounding the ependymal layer is the gray matter – a region containing cell bodies – shaped like the letter “H” or a “butterfly”. The two “wings” of the butterfly are connected across the midline by the dorsal gray commissure and below the white commissure (Figure 3.6). The shape and size of the gray matter varies according to spinal cord level. At the lower levels, the ratio between gray matter and white matter is greater than in higher levels, mainly because lower levels contain less ascending and descending nerve fibers.
The gray matter mainly contains the cell bodies of neurons and glia and is divided into four main columns: dorsal horn, intermediate column, lateral horn and ventral horn column.
The dorsal horn is found at all spinal cord levels and is comprised of sensory nuclei that receive and process incoming somatosensory information. From there, ascending projections emerge to transmit the sensory information to the midbrain and diencephalon. The intermediate column and the lateral horn comprise autonomic neurons innervating visceral and pelvic organs. The ventral horn comprises motor neurons that innervate skeletal muscle.
At all the levels of the spinal cord, nerve cells in the gray substance are multipolar, varying much in their morphology. Many of them are Golgi type I and Golgi type II nerve cells. The axons of Golgi type I are long and pass out of the gray matter into the ventral spinal roots or the fiber tracts of the white matter. The axons and dendrites of the Golgi type II cells are largely confined to the neighboring neurons in the gray matter.
A more recent classification of neurons within the gray matter is based on function. These cells are located at all levels of the spinal cord and are grouped into three main categories: root cells, column or tract cells and propriospinal cells.
The root cells are situated in the ventral and lateral gray horns and vary greatly in size. The most prominent features of the root cells are large multipolar elements exceeding 25 µm of their somata. The root cells contribute their axons to the ventral roots of the spinal nerves and are grouped into two major divisions: 1) somatic efferent root neurons, which innervate the skeletal musculature; and 2) the visceral efferent root neurons, also called preganglionic autonomic axons, which send their axons to various autonomic ganglia.
The column or tract cells and their processes are located mainly in the dorsal gray horn and are confined entirely within the CNS. The axons of the column cells form longitudinal ascending tracts that ascend in the white columns and terminate upoeurons located rostrally in the brain stem, cerebellum or diencephalon. Some column cells send their axons up and down the cord to terminate in gray matter close to their origin and are known as intersegmental association column cells. Other column cell axons terminate within the segment in which they originate and are called intrasegmental association column cells. Still other column cells send their axons across the midline to terminate in gray matter close to their origin and are called commissure association column cells.
The propriospinal cells are spinal interneurons whose axons do not leave the spinal cord proper. Propriospinal cells account for about 90% of spinal neurons. Some of these fibers also are found around the margin of the gray matter of the cord and are collectively called the fasciculus proprius or the propriospinal or the archispinothalamic tract.
Marginal zone nucleus or posterior marginalis, is found at all spinal cord levels as a thin layer of column/tract cells (column cells) that caps the tip of the dorsal horn. The axons of its neurons contribute to the lateral spinothalamic tract which relays pain and temperature information to the diencephalon.
Substantia gelatinosa is found at all levels of the spinal cord. Located in the dorsal cap-like portion of the head of the dorsal horn, it relays pain, temperature and mechanical (light touch) information and consists mainly of column cells (intersegmental column cells). These column cells synapse in cell at Rexed layers IV to VII, whose axons contribute to the ventral (anterior) and lateral spinal thalamic tracts. The homologous substantia gelatinosa in the medulla is the spinal trigeminal nucleus.
Nucleus proprius is located below the substantia gelatinosa in the head and neck of the dorsal horn. This cell group, sometimes called the chief sensory nucleus, is associated with mechanical and temperature sensations. It is a poorly defined cell column which extends through all segments of the spinal cord and its neurons contribute to ventral and lateral spinal thalamic tracts, as well as to spinal cerebellar tracts. The axons originating in nucleus proprius project to the thalamus via the spinothalamic tract and to the cerebellum via the ventral spinocerebellar tract (VSCT).
Dorsal nucleus of Clarke is a cell column located in the mid-portion of the base form of the dorsal horn. The axons from these cells pass uncrossed to the lateral funiculus and form the dorsal (posterior) spinocerebellar tract (DSCT), which subserve unconscious proprioception from muscle spindles and Golgi tendon organs to the cerebellum, and some of them innervate spinal interneurons. The dorsal nucleus of Clarke is found only in segments C8 to L3 of the spinal cord and is most prominent in lower thoracic and upper lumbar segments. The homologous dorsal nucleus of Clarke in the medulla is the accessory cuneate nucleus, which is the origin of the cuneocerebellar tract (CCT).
Intermediolateral nucleus is located in the intermediate zone between the dorsal and the ventral horns in the spinal cord levels. Extending from C8 to L3, it receives viscerosensory information and contains preganglionic sympathetic neurons, which form the lateral horn. A large proportion of its cells are root cells which send axons into the ventral spinal roots via the white rami to reach the sympathetic tract as preganglionic fibers. Similarly, cell columns in the intermediolateral nucleus located at the S2 to S4 levels contains preganglionic parasympathetic neurons.
Lower motor neurouclei are located in the ventral horn of the spinal cord. They contain predominantly motor nuclei consisting of α, β and γ motor neurons and are found at all levels of the spinal cord–they are root cells. The a motor neurons are the final common pathway of the motor system, and they innervate the visceral and skeletal muscles.
3.7 Rexed Laminae
The distribution of cells and fibers within the gray matter of the spinal cord exhibits a pattern of lamination. The cellular pattern of each lamina is composed of various sizes or shapes of neurons (cytoarchitecture) which led Rexed to propose a new classification based on 10 layers (laminae). This classification is useful since it is related more accurately to function than the previous classification scheme which was based on major nuclear groups.
Laminae I to IV, in general, are concerned with exteroceptive sensation and comprise the dorsal horn, whereas laminae V and VI are concerned primarily with proprioceptive sensations. Lamina VII is equivalent to the intermediate zone and acts as a relay between muscle spindle to midbrain and cerebellum, and laminae VIII-IX comprise the ventral horn and contain mainly motor neurons. The axons of these neurons innervate mainly skeletal muscle. Lamina X surrounds the central canal and contains neuroglia.
Rexed lamina I – Consists of a thin layer of cells that cap the tip of the dorsal horn with small dendrites and a complex array of nonmyelinated axons. Cells in lamina I respond mainly to noxious and thermal stimuli. Lamina I cell axons join the contralateral spinothalamic tract; this layer corresponds to nucleus posteromarginalis.
Rexed lamina II – Composed of tightly packed interneurons. This layer corresponds to the substantia gelatinosa and responds to noxious stimuli while others respond to non-noxious stimuli. The majority of neurons in Rexed lamina II axons receive information from sensory dorsal root ganglion cells as well as descending dorsolateral fasciculus (DLF) fibers. They send axons to Rexed laminae III and IV (fasciculus proprius). High concentrations of substance P and opiate receptors have been identified in Rexed lamina II. The lamina is believed to be important for the modulation of sensory input, with the effect of determining which pattern of incoming information will produce sensations that will be interpreted by the brain as being painful.
Rexed lamina III – Composed of variable cell size, axons of these neurons bifurcate several times and form a dense plexus. Cells in this layer receive axodendritic synapses from Aβ fibers entering dorsal root fibers. It contains dendrites of cells from laminae IV, V and VI. Most of the neurons in lamina III function as propriospinal/interneuron cells.
Rexed lamina IV – The thickest of the first four laminae. Cells in this layer receive Aß axons which carry predominantly non-noxious information. In addition, dendrites of neurons in lamina IV radiate to lamina II, and respond to stimuli such as light touch. The ill-defined nucleus proprius is located in the head of this layer. Some of the cells project to the thalamus via the contralateral and ipsilateral spinothalamic tract.
Rexed lamina V – Composed neurons with their dendrites in lamina II. The neurons in this lamina receive monosynaptic information from Aß, Ad and C axons which also carry nociceptive information from visceral organs. This lamina covers a broad zone extending across the neck of the dorsal horn and is divided into medial and lateral parts. Many of the Rexed lamina V cells project to the brain stem and the thalamus via the contralateral and ipsilateral spinothalamic tract. Moreover, descending corticospinal and rubrospinal fibers synapse upon its cells.
Rexed lamina VI – Is a broad layer which is best developed in the cervical and lumbar enlargements. Lamina VI divides also into medial and lateral parts. Group Ia afferent axons from muscle spindles terminate in the medial part at the C8 to L3 segmental levels and are the source of the ipsilateral spinocerebellar pathways. Many of the small neurons are interneurons participating in spinal reflexes, while descending brainstem pathways project to the lateral zone of Rexed layer VI.
Rexed lamina VII – This lamina occupies a large heterogeneous region. This region is also known as the zona intermedia (or intermediolateral nucleus). Its shape and boundaries vary along the length of the cord. Lamina VII neurons receive information from Rexed lamina II to VI as well as visceral afferent fibers, and they serve as an intermediary relay in transmission of visceral motor neurons impulses. The dorsal nucleus of Clarke forms a prominent round oval cell column from C8 to L3. The large cells give rise to uncrossed nerve fibers of the dorsal spinocerebellar tract (DSCT). Cells in laminae V to VII, which do not form a discrete nucleus, give rise to uncrossed fibers that form the ventral spinocerebellar tract (VSCT). Cells in the lateral horn of the cord in segments T1 and L3 give rise to preganglionic sympathetic fibers to innervate postganglionic cells located in the sympathetic ganglia outside the cord. Lateral horeurons at segments S2 to S4 give rise to preganglionic neurons of the sacral parasympathetic fibers to innervate postganglionic cells located in peripheral ganglia.
Rexed lamina VIII – Includes an area at the base of the ventral horn, but its shape differs at various cord levels. In the cord enlargements, the lamina occupies only the medial part of the ventral horn, where descending vestibulospinal and reticulospinal fibers terminate. The neurons of lamina VIII modulate motor activity, most probably via g motor neurons which innervate the intrafusal muscle fibers.
Rexed lamina IX – Composed of several distinct groups of large a motor neurons and small γ and β motor neurons embedded within this layer. Its size and shape differ at various cord levels. In the cord enlargements the number of α motor neurons increase and they form numerous groups. The α motor neurons are large and multipolar cells and give rise to ventral root fibers to supply extrafusal skeletal muscle fibers, while the small γ motor neurons give rise to the intrafusal muscle fibers. The α motor neurons are somatotopically organized.
Rexed lamina X – Neurons in Rexed lamina X surround the central canal and occupy the commissural lateral area of the gray commissure, which also contains decussating axons.
In summary, laminae I-IV are concerned with exteroceptive sensations, whereas laminae V and VI are concerned primarily with proprioceptive sensation and act as a relay between the periphery to the midbrain and the cerebellum. Laminae VIII and IX form the final motor pathway to initiate and modulate motor activity via α, β and γ motor neurons, which innervate striated muscle. All visceral motor neurons are located in lamina VII and innervate neurons in autonomic ganglia.
Surrounding the gray matter is white matter containing myelinated and unmyelinated nerve fibers. These fibers conduct information up (ascending) or down (descending) the cord. The white matter is divided into the dorsal (or posterior) column (or funiculus), lateral column and ventral (or anterior) column (Figure 3.8). The anterior white commissure resides in the center of the spinal cord, and it contains crossing nerve fibers that belong to the spinothalamic tracts, spinocerebellar tracts, and anterior corticospinal tracts. Three general nerve fiber types can be distinguished in the spinal cord white matter: 1) long ascending nerve fibers originally from the column cells, which make synaptic connections to neurons in various brainstem nuclei, cerebellum and dorsal thalamus, 2) long descending nerve fibers originating from the cerebral cortex and various brainstem nuclei to synapse within the different Rexed layers in the spinal cord gray matter, and 3) shorter nerve fibers interconnecting various spinal cord levels such as the fibers responsible for the coordination of flexor reflexes. Ascending tracts are found in all columns whereas descending tracts are found only in the lateral and the anterior columns.
Four different terms are often used to describe bundles of axons such as those found in the white matter: funiculus, fasciculus, tract, and pathway. Funiculus is a morphological term to describe a large group of nerve fibers which are located in a given area (e.g., posterior funiculus). Within a funiculus, groups of fibers from diverse origins, which share common features, are sometimes arranged in smaller bundles of axons called fasciculus, (e.g., fasciculus proprius [Figure 3.8]). Fasciculus is primarily a morphological term whereas tracts and pathways are also terms applied to nerve fiber bundles which have a functional connotation. A tract is a group of nerve fibers which usually has the same origin, destination, and course and also has similar functions. The tract name is derived from their origin and their termination (i.e., corticospinal tract – a tract that originates in the cortex and terminates in the spinal cord; lateral spinothalamic tract – a tract originated in the lateral spinal cord and ends in the thalamus). A pathway usually refers to the entire neuronal circuit responsible for a specific function, and it includes all the nuclei and tracts which are associated with that function. For example, the spinothalamic pathway includes the cell bodies of origin (in the dorsal root ganglia), their axons as they project through the dorsal roots, synapses in the spinal cord, and projections of second and third order neurons across the white commissure, which ascend to the thalamus in the spinothalamic tracts.
Spinal Cord Tracts
The spinal cord white matter contains ascending and descending tracts.
Ascending tracts. The nerve fibers comprise the ascending tract emerge from the first order (1°) neuron located in the dorsal root ganglion (DRG). The ascending tracts transmit sensory information from the sensory receptors to higher levels of the CNS. The ascending gracile and cuneate fasciculi occupying the dorsal column, and sometimes are named the dorsal funiculus. These fibers carry information related to tactile, two point discrimination of simultaneously applied pressure, vibration, position, and movement sense and conscious proprioception. In the lateral column (funiculus), the neospinothalamic tract (or lateral spinothalamic tract) is located more anteriorly and laterally, and carries pain, temperature and crude touch information from somatic and visceral structures. Nearby laterally, the dorsal and ventral spinocerebellar tracts carry unconscious proprioception information from muscles and joints of the lower extremity to the cerebellum. In the ventral column (funiculus) there are four prominent tracts: 1) the paleospinothalamic tract (or anterior spinothalamic tract) is located which carry pain, temperature, and information associated with touch to the brain stem nuclei and to the diencephalon, 2) the spinoolivary tract carries information from Golgi tendon organs to the cerebellum, 3) the spinoreticular tract, and 4) the spino-tectal tract. Intersegmental nerve fibers traveling for several segments (2 to 4) and are located as a thin layer around the gray matter is known as fasciculus proprius, spinospinal or archispinothalamic tract. It carries pain information to the brain stem and diencephalon.
Descending tracts. The descending tracts originate from different cortical areas and from brain stem nuclei. The descending pathway carry information associated with maintenance of motor activities such as posture, balance, muscle tone, and visceral and somatic reflex activity. These include the lateral corticospinal tract and the rubrospinal tracts located in the lateral column (funiculus). These tracts carry information associated with voluntary movement. Other tracts such as the reticulospinal vestibulospinal and the anterior corticospinal tract mediate balance and postural movements. Lissauer’s tract, which is wedged between the dorsal horn and the surface of the spinal cord carry the descending fibers of the dorsolateral funiculus (DFL), which regulate incoming pain sensation at the spinal level, and intersegmental fibers. Additional details about ascending and descending tracts are described in the next few chapters.
Information from the skin, skeletal muscle and joints is relayed to the spinal cord by sensory cells located in the dorsal root ganglia. The dorsal root fibers are the axons originated from the primary sensory dorsal root ganglion cells. Each ascending dorsal root axon, before reaching the spinal cord, bifurcates into ascending and descending branches entering several segments below and above their own segment. The ascending dorsal root fibers and the descending ventral root fibers from and to discrete body areas form a spinal nerve. There are 31 paired spinal nerves. The dorsal root fibers segregate into lateral and medial divisions. The lateral division contains most of the unmyelinated and small myelinated axons carrying pain and temperature information to be terminated in the Rexed laminae I, II, and IV of the gray matter. The medial division of dorsal root fibers consists mainly of myelinated axons conducting sensory fibers from skin, muscles and joints; it enters the dorsal/posterior column/funiculus and ascend in the dorsal column to be terminated in the ipsilateral nucleus gracilis or nucleus cuneatus at the medulla oblongata region, i.e., the axons of the first-order (1°) sensory neurons synapse in the medulla oblongata on the second order (2°) neurons (iucleus gracilis or nucleus cuneatus). In entering the spinal cord, all fibers send collaterals to different Rexed lamina.
Axons entering the cord in the sacral region are found in the dorsal columear the midline and comprise the fasciculus gracilis, whereas axons that enter at higher levels are added in lateral positions and comprise the fasciculus cuneatus. This orderly representation is termed “somatotopic representation”.
Functionally-structural characteristic of spinal cord.
a) Functions, macroscopic structure (The functions of spinal cord are transmitting the impulses and reflectory function. Spinal cord has segmental structure. It consists of 31-33 segments: 8 cervical, 12 thoracic, 5 lumbal, 5 sacral and from 1 to 3 coccigea. Every segment has two pairs of ventral and dorsal roots: right and left. In outer layer present the white substance, where pass conduction tracts, and in inner layer present grey matter, where present nucleus. Segmental principle of work connects with segmental structure of spinal cord. Spinal reflexes are reflexes, which reflex arcs are locked on level of segment of spinal cord. They are tendinous and dermal reflexes. For example, knee reflex is locked on LIII-LIV level. Reflexes between segments whose reflex arcs are locked on many segments. For example, vessels` reflex – on ThI– LII level.)
b) Property of neurons elements (Body of sensory cell are present outside the spinal cord. Some of them are present in spinal ganglion (they innervate the sceletal muscles). Other is present in extra- and intramural ganglions of autonomic nervous system and provide sensitivity of inner organs. The nervous fibers of sensory cells may be myelinated (v=12-120 m/s) and nonmyelinated (v=2 m/s). They go to spinal cord from pain, chemo- and some mechanoreceptors. 3 % of all neurons are moving, 97 % are interneurons. There are α- and γ-motoneurons. α-motoneurons transmit signals from spinal cord to celetal muscles. γ-motoneurons (30 %) innervate intrausal muscles fibers. Excitement of the fibers lead to the contraction or relaxation of extrafusal muscles fibers.)
c) Interposed of afferent and efferent fibers on peripheral part (Bell-Magandy`s law: in the spinal cord the dorsal are sensory, the ventral roots are motors. Quantity of sensory fibers in posterior roots in 20 times more than moving in arterior.)
Reflectory activity of spinal cord.
a) Elicity and reflectory arc of miotatic reflexes: elbow, knee, achill (Spinal somatic reflexes are totally of simple pose and motor acts, which can be realized without participation of higher parts of central nervous system. Stretch reflexes are monosynaptic. Extention, flexor reflexes – polysynaptic, spinal locomotor reflexes are transference. They provide by the help of coordinated movements of limbs. Programated on spinal level it is autonomic movement. Characteristics of elbow, knee, Achilles, plantar and abdominal reflexes. Elbow, knee, Achilles reflexes are monosynaptic, myotatic reflexes. They have segmental character. They are locked on level: elbow – CV– CVI , knee – LII– LIV, Achilles SI– SII.
Plantar and abdominal are dermal monosynaptic reflexe. Are locked on level: plantar – Th12. Superior abdominal Th8 – Th9, medius abdominal Th9–Th10, inferior abdominal – Th11–Th12.
Reflex arcs of tendinous relflex are: knee reflex – intrafusal fibers of m. quadriceps femoris – n. femoralis – LII – LIV – n. femoralis – extrafusal fibers of m. quadriceps femoris.
Achilles reflex – intrafusal fibers of m. gastrocnemius – n. ischiadicus – SI-SII – n. tibialis – extrafusal fibers of m. gastrocnemius.
Elbow flexor reflex – intrafusal fibers of m. biceps brachii – n. musculocutaneus – CV-CVI – n. musculocutaneus – extrafusal fibers of m. biceps brachii.
Elbow extension reflex – intrafusal fibers of m. triceps brachii – n. radialis – CVII-CVIII – n. radialis – extrafusal fibers of m. triceps brachii.
b) Mechanism of development of miotatic reflexes (Muscle spindle consist of nucleus bag (central part) and intrafusal muscles fibers. Spindles connect to the exstrafusal fibers. The quantity of spindles increase in the case of direct muscles’ moving. In the nucleus bag present nervous ending (like-spirale), this has receptor function. From begining of afferent fiber, which transmit excitement fast. Nervous ending may excited in the case of cotraction of muscles fibers. γ-motoneurons have the influence on contraction of it too. γ-motoneurons help to contract the intrafusal fibers. This is a course of stretch of nervous ending iucleus bag. The quantity of impulses to spinal cord is increase. Sensor neurons end near α-motoneurons, excite them and as result extrafusal fibers are contract. This is a base of myotatic reflexes.)
c) Meaning of invistigation of spinal reflexes (It very important for neurologic department to determing the place of destruction of spinal cord.)
d) Bent and cross-unbend reflexes (Cross-unbend reflexes are in the base of locomotor acts and characterised by inhibition of motoneurons of extensor muscles in the same time of excitement of motoneurons of flexor muscles. At this time on the leg and arm of opposite side present opposite reaction. In the stretch reflexes more high tone are in muscles extensor. They help support the static and pose of body.)
Functional meaning of spinal cord’ tracts (There are 2 kinds of tracts: ascendens and descendens. Ascendens tract are sensory, descendens are motor.)
a) Ascendens (Ascending tracts are sensory. They conduct information from external environment to the higher situated centers of encephalon. They are conductors of information from enternal surroundings to the higher part of central nervous system. Goll`s tract (fasciculus gracilis), Burdach`s tract (fasciculus cuneatus) are situated in postirior columnus. They are conducters of tactive and proprioceptive (for example, muscles-elbow) sensorities from down and upper part of the body. Tractus spinothalamicus is situated in lateral columnus. They carry pain, temperature – tractus spinothalamicus dorsalis and spinotectalis – and tactil – tractus spinothalamicus ventralis – sensetivities from body to thalamus.)
b) Descendens (Descending tracts are motors. Corticospinal tract (tractus corticospinalis lateralis) is basic motor tract. It is passing in side columns. It is a conductor of impulses to the skeletal muscles, is regulating free movements.
Monacow`s tract (rubrospinalis) – in side columns, regulate tone of skeletal muscles.
Tractus vestibulospinal dorsalis is present in side columns regilate equilibrium and supporting of pose. Olivospinal tract – in side columns – may be takes part in thalamospinal reflexes. Reticulospinal tract – in front columns – is regulating the tone of skeletal muscles, vegetative spinal centers. Vestibulospinal tract – in front columns – regulates equilibrium and supporting of pose.)
