III. The Mechanism of Muscle Contraction (Pages 2-13) A. Excitation and Contraction - Crossbridge Cycling (Pages 2-8)

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1 Content Display Unit 3 - Skeletal Muscle : Lesson 2 KINE xxxx Exercise Physiology 4 Unit 3 - Skeletal Muscle 3 Lesson 2 1 U3L2P1 - Introduction to Unit 3 - Lesson 2 Lesson 2 addresses the basic mechanism of how muscle develops force during contraction, as well as the uses of energy in contraction. You should recognize that the entire study of energy metabolism (Unit 2) relates to how energy is made available in usable form for muscle. The topic of energetics in this lesson deals with the specific ways that muscle fibers use the energy provided in metabolism. Contents of Lesson 2: Description Page Introduction to Unit 3 - Lesson The Mechanism of Muscle Contraction 3-15 Energetics of Skeletal Muscle Contraction Review of Lesson 23 Outline of Content III. The Mechanism of Muscle Contraction (Pages 2-13) A. Excitation and Contraction - Crossbridge Cycling (Pages 2-8) B. Twitch, Summation, and Tetanus (Pages 9-13) IV. Energetics of Skeletal Muscle Contraction (Pages 14-20) 2 U3L2P2 1 of 18 5/17/2001 3:39 PM

2 - Introduction to Unit 3 - Lesson 2 (cont.) Learning Objectives After completion of Lesson 2, the student should be able to: 1. Describe the basic mechanism of muscle fiber contraction. In your description, include the following: the roles or involvement of ATP, myosin, actin, the troponin-tropomyosin complex, calcium, the sarcoplasmic reticulum, the calcium pump, the sodium-potassium pump, the sarcolemma, action potential. 2. Define the following with reference to skeletal muscle: twitch, summation, tetanus. Discuss the relationship among these and explain the mechanism. Describe the common features by which a twitch is characteristics, and explain the determinant of each feature. 3. List the three activities of muscle fibers that account for nearly all the energy demand during contraction. Explain the reason energy is required for each activity. State the relative contribution of each to the total energy required during muscle contraction. 4. Contrast concentric and eccentric muscle contractions in terms of the crossbridge cycle and the energy demand. 3 U3L2P3 - The Mechanism of Muscle Contraction Excitation and Contraction - Crossbridge Cycling Much of the mechanism of contraction of a skeletal muscle fiber should be apparent after our study of functional anatomy. In this section I will put it all together and summarize the steps involved in contraction. Muscle contraction normally involves an electrical event that leads to a mechanical event. The electrical event is usually referred to as excitation. The mechanical event is force development by very many individual actin-myosin molecular force generators. How the electrical event leads to force development is termed excitation-contraction coupling. 4 U3L2P4 2 of 18 5/17/2001 3:39 PM

3 Excitation and Contraction - Crossbridge Cycling (cont.) Before summarizing the entire process, I want to give a few more details about the electrical excitation of the muscle fiber. An electrical impulse conducted along the sarcolemma is called an action potential. An action potential involves changes in the relative charge (voltage) on one side of the membrane compared with the other (referred to as transmembrane potential). This change in charge results from movement of ions (charged particles) through specialized protein channels in the membrane. The primary movement of ions that leads to stimulation (depolarization) and then contraction of a fiber is a rush of sodium ions from the extracellular fluid into the fiber. The primary movement of ions that returns the sarcolemma to its resting state so it can be stimulated again (i.e., repolarization) is movement of intracellular potassium ions outward. So, a single impulse or action potential involves sodium rushing inward followed by potassium moving outward, all within a few milliseconds. Very small portions of the total amounts of sodium and potassium move across the sarcolemma in a single action potential. But in continuous muscle activity there may be as many as 100 action potentials every second. In these cases, it would not take long for major changes in sodium and potassium concentrations to occur, which would prevent the muscle from functioning normally. Plus, other tissues, such as the heart, would be affected by these electrolyte changes. Maintenance of normal sodium and potassium concentrations in and around the muscle fiber is the function of the sodium-potassium pumps of the sarcolemma. These pumps are not needed for a single muscle action potential, but they are essential over the long term for maintaining the proper concentrations of these important electrolytes. 5 U3L2P5 3 of 18 5/17/2001 3:39 PM

4 Excitation and Contraction - Crossbridge Cycling (cont.) The muscle action potential is initiated at the motor endplate in response to an action potential in the alpha motor neuron that innervates the muscle fiber. The neuron action potential causes release of acetylcholine from the axon ending, and this acetylcholine binds to special protein receptors on the sarcolemma of the motor endplate. This binding leads to depolarization of the sarcolemma due to movement of extracellular sodium into the fiber through special sodium channels. This is called an endplate potential. The endplate potential normally initiates the muscle action potential that is then conducted away from the motor endplate over the entire sarcolemma. The muscle action potential leads to changes in the membrane of the SR inside the fiber so that calcium is released from the SR into the myoplasm. It is this release of calcium from the SR that couples the electrical event of excitation to the mechanical event of contraction. 6 U3L2P6 Excitation and Contraction - Crossbridge Cycling (cont.) (Ref. Fig in Powers & Howley.) Following is a summary of the steps of excitation and contraction of a skeletal muscle fiber. Motor neuron action potential à Muscle fiber motor endplate potential à Muscle action potential à Release of calcium from SR à Binding of calcium to Tn-Tm complex à Change in Tn-Tm complex to allow access of myosin heads to actin binding sites à Binding of myosin head to actin à Pulling on thin filament (actin) by thick filament (myosin) As long as myoplasmic [Ca ++ ] remains high, the Tn-Tm complex will not interfere with myosin-actin binding. For myoplasmic [Ca ++ ] to remain high, there must be repeated action potentials that lead to continual release of calcium from the SR, because the SR calcium pumps are continually pumping calcium out of the myoplasm. Elevated myoplasmic [Ca ++ ] allows repeated interaction of myosin and actin (i.e., contraction), unless the supply of ATP is depleted. Let s look at contraction in more detail, assuming a continued elevation of myoplasmic [Ca ++ ]. 4 of 18 5/17/2001 3:39 PM

5 7 U3L2P7 Excitation and Contraction - Crossbridge Cycling (cont.) (Ref. Fig in Powers & Howley.) Contraction involves a cycle of myosin-actin binding, pulling on actin by myosin, detachment of myosin and actin, and reattachment. This is really a series of chemical reactions that can be summarized as follows. This cycle of chemical reactions is commonly termed crossbridge cycling. Crossbridge refers to the portion of the myosin molecule that connects the thick and thin filament. 8 U3L2P8 5 of 18 5/17/2001 3:39 PM

6 Excitation and Contraction - Crossbridge Cycling (cont.) Following are explanatory notes related to the steps of crossbridge cycling. I have presented more details than I expect you to know, and I will not ask you on an exam to write these precise reactions. This is presented to enhance your understanding of the crossbridge cycle, how myosin and actin interact, and how ATP is involved. Step 1 (Actin-Myosin Binding): A + (M ADP P) à A M ADP P With ADP and P loosely attached, myosin has a very high affinity for actin and is in its high-energy, cocked conformation; in other words, myosin is ready to generate force. But actin-myosin binding can only occur if the Tn-Tm complex moves out of the way. This step is blocked by the Tn-Tm complex when calcium is not bound to troponin; during relaxation, the cycle stops before this reaction takes place. Step 2 (Product Release): A M ADP P à A M + ADP + P Step 2 is when myosin pulls on the thin filament and the actual force-development we know as contraction occurs. The release of the ADP and P results in a conformational change in the myosin head, analogous to pulling the trigger causing the hammer of a revolver to snap back. This converts potential energy to mechanical work. 9 U3L2P9 6 of 18 5/17/2001 3:39 PM

7 Excitation and Contraction - Crossbridge Cycling (cont.) Step 3 (ATP-Binding to Myosin): A M + ATP à A M ATP (low affinity of myosin for actin) Step 3 is when ATP is actually used, although it is not hydrolyzed in this step. The loose binding of ATP to myosin in this step causes the myosin-actin bond to break. If no ATP is available for this step, myosin and actin remain attached. This is referred to as rigor. This may seem good, in that the muscle s force is maintained. Unfortunately, it is maintained without control. Rigor is continuous force development, so the muscle becomes very stiff. One example of rigor is rigor mortis (literally, the rigor of death ). Soon after an organism dies, ATP becomes depleted and it can t be replenished. As a result, muscles become stiff because many myosin heads attach irreversibly to actin molecules. All muscle rigor is not rigor mortis (i.e., resulting from the death of the tissue), but when rigor occurs (before or after death), the muscle is nonfunctional. This emphasizes the importance of having metabolic methods for continually replenishing ATP as it is used. Total depletion of ATP would be catastrophic for a muscle fiber. Step 4 (Actin-Myosin Dissociation & Hydrolysis of ATP): A M ATP à A + (M ADP P) (high affinity of myosin for actin) In Step 4, myosin detaches from actin, and ATP is hydrolyzed. The chemical energy from ATP is used to change the conformation of the myosin head, cocking it in a high-energy state like the cocking of a hammer on a revolver. In other words, chemical energy from ATP is transformed to potential energy in the myosin head. Recall that myosin has ATPase activity, which is stimulated by actin. This catalyzes the ATP hydrolysis in this step. 10 U3L2P10 7 of 18 5/17/2001 3:39 PM

8 Excitation and Contraction - Crossbridge Cycling (cont.) (Ref. Fig in Powers & Howley.) Crossbridge cycling continues as long as myoplasmic [Ca ++ ] is high and ATP is available. As long as the cycle continues, the muscle fiber is contracting. If the steps above occur during a concentric contraction, a given myosin head pulls on the attached actin, causing the thin filament to slide across the thick filament. When the head detaches and reattaches, it reattaches to another actin binding site nearer to the origin of the thin filament on the Z-disk. Thus the adjacent Z-disks are pulled toward each other one step at a time. This is analogous to the action of a ratchet wrench. During eccentric contractions, the bond between myosin and actin is often broken mechanically by the pulling on the thin filament by the larger opposing force. When this happens, ATP does not have to bind to myosin to break the bond, and the myosin head reattaches to an actin site farther from the Z-disk. Thus the adjacent Z-disks are pulled away from each other by the opposing force, but this is resisted by the cyclic attachment of myosin to actin. Note that less ATP is used in these eccentric contractions. This is a major reason why it is metabolically less costly to lower a weight than to lift a weight, or to run downhill than to run uphill. How this mechanism operates during static contractions is not certain. It is known that static contractions have a very high metabolic cost, so the steps involving use of ATP must occur during static contractions. Probably there is movement of the filaments as during concentric contractions while myosin is attached to actin, with sliding back of the filaments when myosin and actin are not attached. The net result is no detectable change in length of the muscle fiber or the entire muscle organ. It is important to remember that there are many millions of myosin heads in the typical fiber. Even when all are active, they cycle asynchronously. At any given instant, many are attached, but some are detached. Thus, in a static contraction, while some myosin heads are detached, recharging to attach to actin again, other myosins are attached and holding the fiber length constant against the opposing load. 11 U3L2P11 8 of 18 5/17/2001 3:39 PM

9 Twitch, Summation, and Tetanus (Ref. Fig & 8.18 in Powers & Howley.) The simplest contraction of a muscle fiber, motor unit, or whole muscle is a twitch. In normal movements of the body, rarely are simple twitches involved. Nevertheless, understanding the mechanism of a twitch is necessary in order to understand more typical muscle contractions. A twitch is a single, brief contraction (force development) by a muscle fiber, motor unit, or whole muscle, following by relaxation. A twitch follows a single, brief electrical stimulus that excites the muscle. When a relaxed muscle or fiber is stimulated, force or tension is generated after a very brief delay. This force increases over time and then decreases back to the pre-stimulus level. A twitch is described by its peak tension, the time to peak tension (contraction time; this is what the terms fast-twitch and slow-twitch refer to), and speed of relaxation. 12 U3L2P12 Twitch, Summation, and Tetanus (cont.) From our study of the mechanism of contraction, the mechanism of the twitch should be clear. The external electrical stimulus initiates an action potential on the sarcolemma. This leads to release of calcium from the SR, but it takes a few milliseconds for the action potential to travel along the sarcolemma and have its effect on the SR, for the calcium to be released from the SR and attach to the Tn-Tm complex, and for the Tn-Tm complex to move out of the way so myosin can bind to actin. This is the brief delay after stimulation before force development begins in the twitch. Force is developed but only for a brief time, after which it decreases again. Why? The twitch is the response to only a single stimulus. So there is only a single action potential on the sarcolemma, leading to just a pulse of calcium released from the SR. And the calcium pumps return this calcium to the SR very quickly. So, myoplasmic [Ca ++ ] is elevated for only a brief period. Therefore, calcium is bound to the Tn-Tm complex only briefly, and the complex quickly returns to its position inhibiting myosin-actin binding. As the final result, myosin-actin binding ceases, that is, contraction stops. 13 U3L2P13 9 of 18 5/17/2001 3:39 PM

10 Twitch, Summation, and Tetanus (cont.) Let s look at the major features of a twitch and their determinants. The time to peak tension or speed of the twitch depends especially on two factors. One factor is the speed at which calcium is released from the SR into the myoplasm. This is determined by the amount of SR in the muscle fiber and by characteristics of certain SR membrane proteins. The other major factor is the type or form of myosin. Some forms of myosin molecules have faster crossbridge cycling rates than others. A major factor that determines potential rate of crossbridge cycling is activity of the enzyme ATPase. For crossbridges to cycle rapidly, ATP must be hydrolyzed rapidly. Therefore, the activity of the enzyme ATPase must be high. We will study this further in a later lesson dealing with different types of muscle fibers. The rate of relaxation depends primarily on the speed at which calcium is pumped out of the myoplasm into the SR. This, in turn, depends on the amount of SR membrane and number of protein pumps. The peak tension developed in a twitch depends on the number of myosin-actin attachments that occur simultaneously in parallel with each other. Therefore, the peak tension of a single fiber largely depends on the cross-sectional area of myofibrils, and the peak twitch tension of a whole muscle depends on the cross-sectional area of active fibers in the muscle. The peak tension of a motor unit depends very much on the size of the motor unit. 14 U3L2P14 10 of 18 5/17/2001 3:39 PM

11 Twitch, Summation, and Tetanus (cont.) The twitch is an all-or-none-response by muscle tissue. Either a stimulus fails to elicit a muscle action potential and therefore no contraction results, or the stimulus elicits an action potential with the sequence of events leading ultimately to the twitch. There cannot be half of a twitch, or two-thirds of a twitch. For a given state of the muscle tissue involved, a twitch will be the same every time. In response to a single electrical stimulus, force output will be either zero (if the stimulus was inadequate) or twitch force. Of course, whole muscles in the intact body don t function this way. Muscles can exert every amount of force between 0% and 100% of maximal force. We will study the regulation of muscle force output in a later lesson. For now, you should understand the twitch response, and understand that twitches cannot be the basis of normal muscle activity. Let me also give a preview of our later study by discussing summation and tetanus. 15 U3L2P15 Twitch, Summation, and Tetanus (cont.) (Ref. Fig in Powers & Howley.) Summation refers to the addition of muscular forces of individual twitches, in response to repeated stimulation. The result is that more force is generated than in a single twitch. How can this happen? The key is myoplasmic [Ca ++ ]. Imagine that a muscle is stimulated and a twitch is elicited. If the muscle is stimulated a second time after peak tension occurs and before the myoplasmic [Ca ++ ] is returned to resting levels by the calcium pumps, a second pulse of calcium is released and more myosin-actin binding occurs before complete relaxation in the original twitch. This is, in a way, a second twitch, but starting from a level of force above the resting level. The force of this twitch is added to the force remaining from the first. And a third twitch could be added on in response to a third stimulus that occurs after peak tension but before total relaxation. And so on. The total force output will depend on the frequency of the stimuli, because this frequency will determine how much calcium is released from the SR and therefore what the myoplasmic [Ca ++ ] is. If the stimulation frequency is high enough, individual twitches can no longer be recognized and the force output is fairly constant. This is called tetanus. There is an optimal rate of electrical stimulation that elicits the highest force output in a sustained manner; this highest force output is called maximal tetanic tension. When this occurs, myoplasmic [Ca ++ ] is kept constant in every active muscle fiber at a level that saturates the 11 of 18 5/17/2001 3:39 PM

12 constant in every active muscle fiber at a level that saturates the Tn-Tm complex, so there can be maximal interactions of myosin and actin. (Recall that as long as [Ca ++ ] is high and ATP is available, crossbridge cycling continues.) 16 U3L2P16 - Energetics of Skeletal Muscle Contraction In the last section we studied the mechanism of contraction of a skeletal muscle fiber. I hope it is clear what the role of ATP hydrolysis is in contraction. I want to summarize this role in this section, and add a few important points. Following are three activities of muscle fibers that require energy from the hydrolysis of ATP during contraction: Crossbridge cycling; the cyclic action of myosin attaching to actin, pulling on actin and the thin filament, releasing, and then reattaching and pulling again. For each of these cycles during concentric and probably static contractions, one ATP molecule must be hydrolyzed. Calcium pumping by the SR membrane. Ion pumping by the sodium-potassium pumps of the sarcolemma. There are other uses of ATP, but quantitatively, these three account for almost all ATP use during contraction. 17 U3L2P17 12 of 18 5/17/2001 3:39 PM

13 - Energetics of Skeletal Muscle Contraction (cont.) At rest, a skeletal muscle fiber uses very little ATP. There is almost no crossbridge cycling; very little calcium escapes from the SR at rest, so there is little calcium to be pumped back into the SR; and relatively little sodium and potassium move across the sarcolemma at rest, so very little sodium-potassium pumping is needed. In fact, if the body is at rest and in an energy-storage state, much of the ATP used by a muscle fiber will be for anabolic processes, such as synthesis of glycogen or triglyceride. But the energy cost of these activities is very low compared to the energy demand of contracting muscle fibers during exercise. The energy demand of muscle is directly proportional to force developed or power output, as illustrated in the graph. I hope it is already fairly clear why this is. Each of the three activities that use large amounts of ATP (crossbridge cycling, calcium pumping, and sodium-potassium pumping) speeds up as muscular activity increases. 18 U3L2P18 13 of 18 5/17/2001 3:39 PM

14 - Energetics of Skeletal Muscle Contraction (cont.) Imagine that I am going to do two bench presses, first with a light (75-pound) weight and then, after a rest interval, with a heavy (200-pound) weight. (OK, so I can t bench press 200 pounds, but I told you to imagine!) Before the exercise, there would be very little ATP use in my triceps brachii muscle (the major elbow extensor muscle). Let s focus only on the lift and ignore the lowering of the weight, for simplicity. As I lift the 75-pound barbell, I need quite a few myosin heads to attach to actin molecules and pull, and I need them to keep cycling until I complete the lift. This greatly increases the demand for energy from ATP. For this increased cycling to continue, there has to be continual release of calcium from the SR, and this increases the rate of calcium pumping. For there to be continual release of calcium from the SR, there has to be repeated action potentials on the sarcolemma. This increases the movement of sodium inward and potassium outward, so the sodium-potassium pump must increase its activity to counteract these ion movements. Now I m ready to press the 200-pound barbell. Much more muscular force is needed than when lifting the 75-pound weight. Therefore, more myosin-actin attachments are needed, more calcium must be released from the SR to keep the increased number of myosin molecules cycling, and more action potentials are needed to cause the increased release of calcium from the SR. Thus, all three of the ATP-requiring activities are increased substantially, so ATP hydrolysis will also be substantially increased above the rate of ATP use during lifting of the 75-pound weight. 19 U3L2P19 14 of 18 5/17/2001 3:39 PM

15 - Energetics of Skeletal Muscle Contraction (cont.) What are the relative ATP requirements of these three activities during contraction? Crossbridge cycling accounts for about 65-70% of the ATP used. Calcium pumps account for about 20-30% of the ATP used. Sodium-potassium pumps account for about 5-10% of the ATP used. These proportions vary depending on the types of exercise and on the particular muscles. (We will study different types of muscle fibers later in this unit.) 20 U3L2P20 - Energetics of Skeletal Muscle Contraction (cont.) Let me try to give some perspective to the range of energy requirements of skeletal muscles. When the body is at rest, such as sitting quietly in a chair or lying down, all of the skeletal muscles in the body account for about 20% of the body s total energy turnover. Since skeletal muscles may make up 25-50% of total body mass (depending on body composition and muscular development), this indicates that resting skeletal muscle has a relatively low metabolic rate. During intense exercise using a large portion of the body s skeletal muscles, muscle may account for 90% of the total energy turnover. In other words, the increase in energy turnover in skeletal muscle fibers is huge. Energy turnover in some contracting fibers may increase more than 200 times above the resting rate! You may have heard comparisons of muscle tissue with fat (adipose) tissue in terms of metabolic rate. Sometimes muscle is made to sound as though it burns lots of calories just because it s there. It is true that fat cells have very low metabolic rates. For one thing, the actual cellular material of fat (not counting the triglycerides stored inside) is quite small. Secondly, fat cells don t do much that requires energy, at rest, during exercise, or at any other time. Skeletal muscle tissue has a higher resting metabolic rate, but it is still low. Large amounts of energy are turned over by muscles only when they are contracting, that is, during exercise. 21 U3L2P22 15 of 18 5/17/2001 3:39 PM

16 - Energetics of Skeletal Muscle Contraction (cont.) Let me remind you of the methods available to muscle fibers for the replenishment of ATP, which we studied in the unit on metabolism: the CK reaction, anaerobic glycolysis, and aerobic metabolism. I hope you see the essential relationship between muscle contraction and replenishment of ATP by some combination of those methods. During exercise, muscle contraction absolutely must have ATP available at a certain rate to support crossbridge cycling and pumping of ions. And the replenishment systems absolutely must make ATP at the same rate, or the small amount of ATP that is present in muscle fibers will quickly be used up. Then the muscle fibers could not function at all. Of course, in normal muscles, regulatory systems will adjust contractile activity downward (i.e., reduce muscle force and/or velocity of contraction), as necessary, to reduce the rates of crossbridge cycling and ion pumping, so the rate of ATP use matches the rate of ATP formation. We recognize this as muscular fatigue. 22 u3l2p22 - Energetics of Skeletal Muscle Contraction (cont.) Let me make one or two more comments about differences between concentric and eccentric muscle contractions. When a certain weight is lifted a given distance and then lowered the same distance, exactly the same external work is done, with one exception. The exception is that positive work is done when the weight is lifted and negative work is done when the weight is lowered. Because the absolute quantities of work are the same, the total tensions or forces in the active muscles are about the same when lifting and lowering the same weight. But, the rate of ATP use (i.e., metabolic cost) during eccentric contractions is less than during similar concentric contractions. Note the difference in energy cost between concentric work (e.g., lifting weights, walking or running uphill) and eccentric work (e.g., lowering weights, walking or running downhill) in the figure. 16 of 18 5/17/2001 3:39 PM

17 How can the total tensions in active muscles be similar during concentric and eccentric contractions but the metabolic cost be lower during the eccentric contractions? There are two reasons. One reason is that elastic components of muscles provide some of the resistive force during eccentric contractions. Have you ever bungee-jumped? So far, I have passed on this activity! A bungee cord can resist the effect of gravity and stop a person s fall before hitting the ground (or at least it better). But the bungee cord cannot lift the person back up to the starting point again. Elastic energy is used to resist the external force. Muscle can do the same thing because it has elastic elements within it. These include connective tissue, the various membranes of muscle fibers, and even the contractile proteins. These exert force resisting the opposing force during eccentric contractions, but they do not require energy from ATP breakdown. The other reason the metabolic cost of eccentric contractions is lower than the cost of concentric contractions of similar force is that some myosin-actin bonds are mechanically broken by the opposing force in eccentric contractions. The breaking of these bonds during concentric contractions is caused by the binding of ATP to myosin. Some ATP is, of course, used during eccentric contractions, but more is used during concentric and static contractions, as discussed previously. 23 u3l2p23 17 of 18 5/17/2001 3:39 PM

18 - Review of Lesson You have come to the end of the online content of Unit 3 - Lesson 2. When you want to review the concepts in this lesson, use the Learning Objectives on Page 1 of this lesson and the Review Questions below. These should be a good study guide. If you can correctly do what the Objectives and Review Questions ask, you will have mastered the most important concepts in this lesson. Please realize, however, that these do not exhaustively cover all the information in the lesson. If you are uncertain about any Objective or Review Question, or if you want clarification or expansion of any point in the lesson, I urge you to start a threaded conference discussion on WebBoard. Other students may have the same concerns, will probably benefit from the discussion, and may have the information you seek. And, of course, feel free to contact me (Dr. Eldridge) for assistance. Be sure to check the Announcements Page to see whether there is a specific WebBoard or other assignment associated with this lesson. Review Questions 1. One effect of caffeine is to increase the level of calcium in the myoplasm of skeletal muscle. This tends to make muscle fibers more responsive to a stimulus so that they generate more force. Describe a reasonable mechanism for this action of caffeine. 2. Imagine that skeletal muscles could only contract in twitches. Discuss at least two disadvantages of such physiology. Cancel Key: Course Module Lesson Page SubLesson SubLesson Page Copyright 1999 VCampus Corporation All rights reserved. 18 of 18 5/17/2001 3:39 PM