Clinical Note

Muscular Dystrophy

Muscular dystrophy is one of the most common inherited childhood lethal disorders. In most cases, this disorder, characterized by muscle (primarily skeletal muscle) weakness and gradual fibrotic replacement of tissue, is due to mutations in the dystrophin gene. Dystrophin is a large protein that in part comprises the cytoskeleton that is connected to the sarcolemma. Defects in dystrophin are believed to lead to instability of the sarcolemma, making it more susceptible to stress-induced damage especially during contraction. Such damage may then allow loss of intracellular components and/or the influx of calcium in concentrations that induce cell death.

against a constant force is called an isotonic contraction. Isometric and isotonic contractions can be studied in for example, by straining against an immovable vivo-

object (isometric contraction) or by moving a load (isotonic contraction); however, contractions are more easily studied in vitro using isolated strips of muscle.

Skeletal Muscle

Isometric Contraction

A small skeletal muscle, composed of hundreds of individual muscle cells, can be placed in physiologic salt solution with one end connected to a fixed point and the other end connected to a transducer so that the time course and force of isometric contractions can be recorded (Fig. 7). If single, short-duration electric pulses of increasing intensity are delivered to the muscle, a threshold intensity will be reached at which a mechanical response is elicited. This contraction is due to the activation of one or a few of the most excitable muscle cells. As stimulus pulse intensity is increased, contractile force increases up to a point at which further increases in intensity result in no further increase in force. Such pulses are referred to as maximal or supramaximal. This behavior is due to the fact that individual muscle cells

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Contraction force

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Twitch summation

Tetanus

Shock intensity

FIGURE 7 Recording isometric contraction in vitro. A small bundle of skeletal muscle fibers is placed in a warmed, oxygenated physiologic salt solution. One end is anchored to the bottom of the bath and the other end to a movable force transducer. Wires from a stimulator are placed so that the muscle can be excited with electrical pulses. (Top) The muscle is stretched to its in vivo resting length and stimulated with single shocks of increasing intensity. Once a threshold is reached, a single, longer lasting contractile response, called a twitch, results. As simultaneous intensity is progressively increased, contraction forces increase up to a point at which further increases in intensity result in no further increase in force. (Bottom) If shocks that cause a single twitch of maximal force are delivered at a higher frequency, the muscle does not have a chance to relax fully before the second stimulus. This results in the second response generating a greater force (summation). If a series of closely spaced shocks are delivered, muscle force rises smoothly to a maximum and stays elevated (tetanus) until stimulation ceases.

within a muscle bundle differ from one another in their excitabilities, and that excitation of one muscle cell does not spread to other muscle cells. Threshold stimuli induce only the most excitable cells to contract. As stimulus intensity is increased, more cells are recruited until all of the cells comprising the muscle are recruited by maximal and supramaximal stimuli. Although recruitment can be demonstrated in this manner in vitro, as discussed below, recruitment in vivo occurs at the level of the nervous system.

If, instead of using only a single supramaximal pulse, a second supramaximal pulse is delivered before the muscle relaxes from the first stimulation, the second contraction will be larger, a phenomenon known as summation. The magnitude of summation is increased by decreasing the time between successive pulses (i.e., increasing pulse frequency). Eventually, a pulse frequency will be reached that is so high that muscle responses to individual pulses cannot be detected; at this point, a smoothly shaped contraction to a maximum force is obtained that is referred to as a tetanic contraction. Once reached, further increases in pulse frequency will not increase peak contractile force.

The phenomena of summation and tetanus occur because: (1) the time courses of excitation, excitation-contraction coupling, and activation of the contractile proteins are different; and (2) structures with elastic properties exist within and between the cycling cross-bridges and the ends of the muscle cells. Each short, supramaximal electrical pulse elicits a single action potential in each muscle cell (Fig. 8). Even though each single action potential lasts only about 1 msec, it results in the release of enough calcium to fully activate the contractile proteins. However, the duration of each calcium pulse is only a few milliseconds. Such a short, but complete, activation of the contractile proteins does allow some crossbridge cycling and sliding of the thick and thin filaments over one another, but such short activation does not allow the full force of this interaction to be transmitted to the ends of the muscle. Also, during an isometric contraction, there is no shortening of the ends of the muscle even though some filament sliding has taken place. How can this be? Muscle proteins have elastic properties much like that of a spring. These structures transmit the forces generated by crossbridge cycling to the ends of the muscle and are stretched as force is developed at the ends of the muscle. This stretching takes energy and time. In response to a single action potential, crossbridge cycling lasts too short a time to stretch these structures fully, so full force is not seen at the ends of the muscle. Although full force is not seen, not all the energy expended in stretching the elastic structures is lost. Much of the energy is stored and released during and after crossbridge cycling, so that the contractile response at the muscle ends has a much slower rise time and a much longer duration than either the action potential or the rise in calcium.

As pulse frequency is increased to produce summation, each pulse still produces a single action potential and an associated rise and fall in calcium. However, the contractile proteins are activated a second time before the elastic structures of the muscle return to their resting state. Thus, the energy of the second contractile protein interaction can stretch the elastic elements more fully and can develop more force at the ends of the muscle. During tetanus, each pulse still is eliciting an action potential, but now calcium levels do not fall between action potentials. The maximum calcium level is no higher than with a single, isolated action potential, but it is maintained for a longer time. The continual level of

FIGURE 8 Action potentials, cytoplasmic calcium levels, and contraction forces of skeletal muscle in response to a single shock (A) and tetanic stimulation (B). Note that each shock is followed by an action potential of identical amplitude and duration and by an increase in calcium to its maximal level. However, the time that calcium levels are increased is greater during the tetanus. This is in part the cause of the increased force during tetanus. (Modified from Berne RM, Levy MN, Physiology, 2nd ed. St. Louis: Mosby, 1988.)

Tetanic Stimulation (Multiple Shocks)

FIGURE 8 Action potentials, cytoplasmic calcium levels, and contraction forces of skeletal muscle in response to a single shock (A) and tetanic stimulation (B). Note that each shock is followed by an action potential of identical amplitude and duration and by an increase in calcium to its maximal level. However, the time that calcium levels are increased is greater during the tetanus. This is in part the cause of the increased force during tetanus. (Modified from Berne RM, Levy MN, Physiology, 2nd ed. St. Louis: Mosby, 1988.)

calcium allows for continual activation of the contractile proteins, so that elastic elements can be stretched completely and the full force of crossbridge cycling can be realized at the ends of the muscle.

The force of contraction also depends on the resting length of the muscle. If the relaxed muscle is hung in the bath so that it is at the shortest length at which it hangs straight, no resting force is recorded by the transducer. If the relaxed muscle is slowly stretched by moving the force transducer, the resting force remains at almost imperceptible levels over the initial changes in length, then force increases exponentially with further stretch. The curve generated by such stretching describes the length-passive force (sometimes called passive length-tension) relationship (Fig. 9). Note that this curve is similar to that seen for any elastic body. Another curve will be obtained if the experiment is repeated, only this time stretching the muscle in steps and, at each level of stretch, stimulating with pulses of supramaximal intensity at a frequency that will produce tetanus. If the peak force during tetanus at each length is plotted, the length-total force relationship is obtained. Total force at each length is the sum of the passive force (defined

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