ELECTROPHYSIOLOGY OF MUSCLES
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
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.
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.
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.
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.
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.
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.
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.
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 neuroormally 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 upoeuromuscular 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.
