3

SERCA

The pump that is responsible for maintaining intracellular [Ca²⁺] at a very low level (<90 nM) is also known as the sarcoendoplasmic reticulum Ca²⁺ ATPase (SERCA). This pump is known as a uniporter because it transfers just one kind of ion (Ca²⁺) across a membrane in one direction. The density of SERCA on the surface of the sarcoplasmic reticulum is so high that there is little room for other proteins in this fenestrated organelle. Like most ion pumps, the energy needed to pump Ca²⁺ across the sarcoplasmic reticulum membrane is provided by ATP. For each ATP hydrolyzed by this pump, two Ca²⁺ ions are transferred into the sarcoplasmic reticulum. The energy cost of transporting Ca²⁺ can account for up to 30% of the energy cost of muscle contraction. See the research highlight near the end of this chapter to see how this is experimentally determined. Any time ATP is split, there is some energy released as heat. This fact can explain the condition known as malignant hyperthermia (Gronert, 1980). Certain agents like halothane, a volatile anesthetic, can trigger widespread leak of Ca²⁺ from the sarcoplasmic reticulum, activating the SERCA and triggering actin-myosin ATPase activity. Due to the large rate of ion pumping throughout the body and cross-bridge cycling, and corresponding heat release, body temperature can rise to lethal levels. In spite of the fact that an antidote is available, halothane is no longer used for general anesthesia.

Sodium–Potassium ATPase

With each activation of a skeletal muscle fibre, some Na⁺ is transferred into the myocyte and some K⁺ is lost to the extracellular fluid. This ion transfer occurs through voltage-gated channels that briefly open, allowing Na⁺ and K⁺ to move down their electrochemical gradients. An increase in extracellular [K⁺] activates the Na⁺–K⁺ ATPase, and ATP is hydrolyzed to provide the energy for ion pumping. This pump can transfer 3 Na⁺ ions and 2 K⁺ ions with each molecule of ATP hydrolyzed. The amount of ATP used by the Na⁺-K⁺ pump can account for up to 10% of the total energy cost of a muscle contraction.

Now that you understand the processes that require energy, it is time to learn how muscle is turned on. As we talk about the process of excitation-contraction coupling (E-CC), it is important to realize that these processes are initiated at all neuromuscular junctions where action potentials have been propagated. This could be very few in a small muscle that is not activated very vigorously, or literally millions of muscle fibres in a large leg muscle that is activated very vigorously.

Excitation-Contraction Coupling

Our muscles are organized in motor units; each fibre is activated by a single motoneuron. Muscles are activated by descending motor pathways that excite the motor nerves of a given muscle in the ventral horn of the spinal cord. Each cell body and the corresponding dendrites will have literally thousands of excitatory and inhibitory nerve endings contributing to excitation or inhibition of the axon hillock, the location of the nerve cell body where the action potential originates. If the axon hillock reaches threshold, sodium and potassium channels will open and an action potential will be generated and propagated along the axon. Motor neurons are myelinated and conduction velocity is very fast (90-110 ms^-1). When an action potential gets to the nerve terminals, the activation is transmitted to the muscle fibre by neuromuscular transmission, a process that results in generation of an action potential on the surface membrane of the muscle fibre, for each action potential arriving at the nerve terminal. The process of activating a skeletal muscle fibre, which includes several steps from generation and propagation of the action potential to mechanical engagement of myosin cross-bridges is a complex process, which will be described after the description of the process involved in neuromuscular transmission.

Neuromuscular Transmission

The process of neuromuscular transmission involves several steps from arrival of the action potential at the nerve terminal to generation of an action potential on the muscle membrane. It is important to realize that these steps will occur at all terminals of the same motoneuron, thereby simultaneously activating all muscle fibres of the motor unit. The number of fibres associated with each motor unit can vary from 10 or so to thousands. Each step in the process of neuromuscular transmission is described below.

Voltage-Gated Calcium Channels

Depolarization of the nerve terminal membrane with arrival of the action potential results in activation (opening) of a few voltage-gated Ca²⁺ channels. These channels open and allow Ca²⁺ to diffuse down its concentration gradient into the nerve terminal from the extracellular space. The result of just a few of these channels opening is that just a “puff” of Ca²⁺ comes into the nerve terminal, near each activated Ca²⁺ channel. This “puff” of Ca²⁺ is sufficient to trigger a sequence of events that result in emptying of a few vesicles into the synaptic cleft at each neuromuscular junction.

Fusion of Docked Vesicles

Vesicles within the nerve terminal contain acetylcholine. These vesicles are distributed such that some are freely floating throughout the nerve terminal, some are tethered close to the membrane across from the muscle and some are docked in this region. Vesicles have specialized proteins in their membrane that react with other specialized proteins in the nerve terminal membrane. Docking of the vesicle in this region is achieved by interaction of these special proteins. The local increase in [Ca²⁺] results in Ca²⁺ binding to one of these proteins that is part of the complex of proteins docking a synaptic vesicle to the nerve terminal membrane. This binding of Ca²⁺ triggers the fusion process; the vesicle membrane becomes nerve terminal membrane (exocytosis), essentially turning inside out and releasing acetylcholine into the synaptic cleft (see Figure 5-5). In a remarkable process of recycling, the membrane that was vesicle but is now part of the nerve terminal membrane can be reused to create a new vesicle. This preserves the specialized proteins needed in the vesicle membrane. The process of reforming the vesicle is called endocytosis.

Binding of Acetylcholine to its Receptors

Acetylcholine is the neurotransmitter of the neuromuscular junction. Once acetylcholine is released, it diffuses across the primary synaptic cleft and into the secondary synaptic clefts. On the postsynaptic membrane, there are specialized receptors for binding acetylcholine. In spite of the fact that only a few Ca²⁺ channels respond to depolarization of the nerve terminal, more than enough acetylcholine is released into the synaptic cleft to cause depolarization of the muscle end-plate region to threshold, resulting in generation of a muscle fibre action potential. This depolarization results from opening of a channel in the acetylcholine receptor that allows both Na⁺ and K⁺ to move across. Due to the fact that the electrochemical gradient for Na⁺ is stronger than for K⁺, more Na⁺ moves across the membrane than K⁺ and this causes depolarization. Once the depolarization reaches about -50 mV, voltage-gated Na⁺ and K⁺ channels open. These are the channels that are responsible for propagation of the action potential across the muscle membrane, spreading in all directions from the neuromuscular junction.

Destruction of Acetylcholine Terminates Neuromuscular Transmission

The neuromuscular junction gap is very confined. Acetylcholine diffuses in this confined area, and is captured by an enzyme “acetylcholinesterase” that splits acetate from the choline. Acetylcholinesterase is tethered to the basement membrane in the end-plate region. As the acetylcholine is split, its concentration will decrease and acetylcholine will be released from its receptor on the muscle surface. This terminates activation of the muscle. Nearly all of the acetylcholine that is released is deactivated by acetylcholinesterase; very little escapes to the surrounding area. Again, the neuromuscular junction has a fabulous recycling program. The choline is transported back into the nerve terminal where it is used to resynthesize new acetylcholine. The recycled vesicles are resupplied with new acetylcholine.

Muscle Membrane Response

An action potential is generated on the muscle plasmalemma, similar to the action potential on an axon. Membrane voltage quickly changes from -85 mV to +20 mV then repolarizes to the normal resting membrane potential. For each axon action potential, there is a muscle fibre action potential that is propagated over the surface membrane of the myocyte at a rate of 2-5 ms^-1. This is quite slow in comparison with a motor axon conduction velocity (~100 ms^-1). The action potential is also conducted into the muscle fibre via the transverse-tubules. The transverse tubules are continuations of extracellular environment into the muscle fibres and encircle the myofibrils. The transverse-tubules are located at regular intervals along the muscle fibre, allowing activation of each sarcomere near the A-I junction. It appears that the transverse-tubules stay approximately 500 nm from the Z-disk as sarcomere length changes (Brown & Loeb, 1999).

There is no energy cost linked directly to the generation and propagation of the action potential. The ions Na⁺ and K⁺ move down their electrochemical gradient when the voltage-gated channels open. However, to preserve the ion concentration gradients, it is necessary to pump these ions back to where they originated; Na⁺ is pumped out of the myocyte and K⁺ is returned from the extracellular space to the cytoplasm. This active transport is achieved by Na⁺–K⁺ ATPase, a transporter that uses energy from ATP to transfer 3 Na⁺ and 2 K⁺ with hydrolysis of each ATP molecule.

Internal Membrane Potentials

The transverse-tubules are continuations of the sarcolemma that go deep into the myocyte, encircling the myofibrils about 500 nm from the Z-disk. The surface action potential is propagated into the transverse-tubules. In addition to the Na⁺ and K⁺ channels in the sarcolemma of the transverse-tubules, this membrane also has dihydropyridine receptors (DHPR) which function as voltage detectors. DHPR are actually modified Ca²⁺ channels, that do not require Ca²⁺ to go through them to serve the function of activating skeletal muscle. Half of the DHPR are linked directly to ryanodine receptors (RYR) which are actually embedded in the membrane of the terminal cisternae, the enlarged portion of the sarcoplasmic reticulum that lies adjacent to the transverse-tubule. The proximity of the terminal cisternae on either side of the transverse-tubule in cell cross-sections as a repeating structure of three membrane bound structures has been given the name of “triad”. This structure is evident in Figure 5-6 where the grey ryanodine receptors are adjacent to the transverse tubule.

Excitation-Contraction Coupling. This diagram illustrates the essential steps in activating a muscle cell: 1. Action potential generation and propagation down the transverse tubules; 2. Detection of T-tubule depolarization by the dihydropyridine receptor; 3. Opening of the ryanodine receptor; 4. Diffusion of Ca²⁺ out of the terminal cisternae into the myoplasm; 5. Binding of Ca²⁺ to troponin C; 6. Translocation of tropomyosin, revealing the myosin binding sites on actin, allowing cross-bridge cycling; and 7. Ca²⁺ pumping by SERCA back into the sarcoplasmic reticulum. Source: Diagram created by Barbara Holash, for “Skeletal muscle fatigue – regulation of excitation-contraction coupling to avoid metabolic catastrophe” in J Cell Science 125: 2105-2114, 2012. Used with permission of the authors.

Calcium Handling in the Muscle Cell

When the DHPR detect the membrane potential change associated with the action potential, they trigger the opening of the RYR to allow Ca²⁺ to move down its concentration gradient from the terminal cisternae into the sarcoplasm. Although this event (Ca²⁺ release) is happening at the sarcomere level of a myofibril, this occurs throughout the myocyte as the action potential is moving across the surface membrane and into all of the transverse tubules. The amount of Ca²⁺ released from the sarcoplasmic reticulum with each activation (action potential) is sufficient to raise the myoplasmic [Ca²⁺] from the resting value of 70 nM to 200 µM. However, the actual increase in free [Ca²⁺] with a single release event like this is less than 1 µM. The reason for this huge discrepancy is that much of the released Ca²⁺ binds immediately to a number of Ca²⁺ buffers in the myoplasm. These buffers include: ATP, calmodulin, SERCA, parvalbumin, and troponin C.

The rise and fall of [Ca²⁺] in the myoplasm is called the calcium transient. In response to a single activation, this calcium transient is very brief; it is over in a few milliseconds. However, when several activations occur in quick succession, the cumulation of calcium transients can result in a sustained elevation of [Ca²⁺].

The buffering of Ca²⁺ by these molecules often has subsequent consequences. For example, binding of Ca²⁺ to calmodulin activates a number of enzymes, like myosin light chain kinase. This topic is further discussed in the chapter on Repetitive Contractions (see Chapter 12). Binding of Ca²⁺ to SERCA results in transfer of Ca²⁺ into the sarcoplasmic reticulum, allowing further binding of Ca²⁺ and decreasing myoplasmic [Ca²⁺]. Binding of Ca²⁺ to troponin-C is the event that activates muscle contraction.

Troponin and Tropomyosin

Troponin-C is a Ca²⁺-binding protein, part of the troponin complex (Troponin C, I, and T) associated with tropomyosin and the thin filament of the sarcomere (see Figure 5-7). The thin filament is composed mostly of actin. Each tropomyosin molecule spans 7 actin filaments, lying over the myosin-binding site. This position blocks binding of myosin to actin. Binding of Ca²⁺ to troponin-C causes a realignment of this protein complex such that tropomyosin is pulled out of the groove between the two actin strands, exposing the binding site for myosin on actin. This allows the cross-bridge cycle to be initiated. The cross-bridge cycle will continue as long as Ca²⁺ is bound to troponin-C.

The thin filament is composed of two strands of sequential actin monomers with tropomyosin spanning 7 actin monomers, blocking the myosin-binding sites. Each myosin molecule is composed of a double-strand S2 segment and two S1 heads, each with ATPase function.

Cross-Bridge Cycle

The exposure of the binding site for myosin on the actin filament permits binding of the myosin head to actin, creating a cross-bridge. The initial binding of the myosin head to actin is considered aweak-binding state. Once the cross-bridge is formed, Pi is ejected from the myosin head and this reaction allows change to the strong-binding state. This transition is also called the power-stroke. The cross-bridge maintains this force generating position until it disengages. Disengagement of the cross-bridge results from the probability of dissociation (g), which increases to a high level if length change is associated with this cross-bridge activity. This letting go requires release of ADP and binding of a molecule of ATP. The binding of ATP to the myosin head allows disengagement of the cross-bridge. The free myosin head now partially splits ATP to ADPPi. This partial splitting causes a structural rearrangement of the myosin head to the cocked position, a structure that can undergo the power stroke, once it is again bound to actin. If the binding site on the actin filament is still available, this now cocked myosin head can bind and undergo another cycle. Cycling of the cross-bridge will continue as long as Ca²⁺ is bound to troponin-C. See Figure 5-8.

The sequence of events associated with activation of the cross-bridge cycle are illustrated. Beginning in the lower left, the myosin heads are lying close to the myosin filament backbone. The tropomyosin is blocking the binding sites for myosin on the actin filament (1 blocked). Phosphorylation of the light chains of myosin will increase the mobility of the myosin heads (2 blocked), increasing the probability of actin-myosin interaction. Addition of Ca²⁺ to the cytoplasm results in binding of Ca²⁺ to troponin, which moves tropomyosin to the “closed” position (2 closed). The myosin head can now bind to actin. Binding of myosin to actin results in activation of myosin ATPase, and Pi is released, allowing a power stroke. Engagement of a myosin head with actin results in further movement of tropomyosin away from the binding sites. This is called the open state (3 open). Subsequent release of ADP and binding of ATP to the myosin head results in dissociation of the myosin head from actin (4 open). The myosin head then partially hydrolyzes the ATP to ADP*Pi resulting in reconfiguration of the myosin head into the cocked position that can attach to actin.

The collective effect of cross-bridge cycling is that force is generated and movement is possible. Force will be generated by each cross-bridge that binds to actin. Total active force will be proportional to the number of cross-bridges bound in parallel (across all parallel sarcomeres). The same force must be generated in all sarcomeres in series. If the resistance to shortening is sufficient, no length change will occur. Once the force generated by the cross-bridges exceeds the resistance, shortening will occur. If the load on the muscle exceeds the force generated by the cross-bridges, lengthening occurs.

Asynchronous Motor Unit Activation

The frequency of action potentials on the motor nerve dictates the frequency of action potentials on the muscle membrane because there is a one-to-one relationship between nerve and muscle action potentials. However, in a voluntary contraction, motor unit activation is asynchronous so the oscillations seen at subfusion frequencies are lost in a smoothing effect of activation of multiple motor units.

Types of Contraction

When a muscle is activated, cross-bridge cycles are initiated and force develops. The type of contraction is called fixed-end if the muscle-tendon length does not change. A truly isometric contraction occurs without muscle fibre length change. However, these two terms (fixed-end and isometric) are sometimes used interchangeably. Often, the term isometric will be used to describe a contraction that does not have length change of the muscle-tendon unit. The muscle-tendon unit will shorten if the load on the muscle is not sufficient to prevent shortening or it will lengthen if the load exceeds the force generated by the muscle. When length change occurs, the contraction is called dynamic. The term “auxotonic” has also been used to describe muscle contraction where the force changes through-out the duration of the contraction and some fibre shortening occurs. A special form of dynamic contraction is one where the velocity of shortening is controlled. This is an isokinetic contraction.

Active and Passive Force and Types of Contraction

When you stretch an inactive muscle, it resists the stretch with a small force that is independent of activation, but this passive force increases with length. This is called passive force and is the property of passive structures like connective tissue, membrane, and titin. When a muscle is activated, cross-bridge cycles are initiated and the force increases above the passive force. In general, muscle physiologists calculate the active force by subtracting the passive from the peak force. This calculation assumes that passive force remains constant during the contraction, and that active force simply adds to the passive force. However, it has been shown that passive force most likely decreases while active force is increasing (MacIntosh & MacNaughton, 2005). This happens because the tendon is stretched slightly as active force develops and the muscle fascicles decrease in length, decreasing the passive force across these passive structures.

Active force is calculated by subtracting the appropriate passive force from the peak force reached during a contraction (MacIntosh & MacNaughton, 2005). This should represent the actual force generated by energy-requiring processes (cross-bridge cycling). The way of calculating active force is illustrated in Figure 5-9. The active force achieved by a given stimulation is dependent on several factors including frequency of activation, [Ca²⁺], sarcomere length, and velocity of length change.

The Isometric Contractile Response

Activation of a muscle results in a contractile response that is dependent on the number and frequency of action potentials propagated across the surface membrane. With each activation, [Ca²⁺] rises and falls, but with increasing frequency, the average [Ca²⁺] achieved will be higher. The voluntary frequency of activation of human muscle is in the range of 8 Hz to 70 Hz, except for brief doublets or triplets (2-3 activations) at higher frequencies, often associated with initiation of ballistic contractions. The response to a single activation is called a twitch contraction while the response to repeated activations without complete relaxation between activations is known as a tetanic contraction.

Twitch Contraction

The rise and fall of active force during a twitch contraction is an elegant contractile response to a single activation (see Figure 5-10). The amplitude of force response depends on several factors, including: sarcomere length, temperature, prior activation (fatigue and activity dependent potentiation) as well as cross-sectional area of the cell, motor unit, or muscle stimulated. The term “twitch” is sometimes used to describe the contractile response to a doublet (two pulses) stimulation when the frequency is high. This alternative use of the term can only be understood by the context of the use, something the learner in exercise physiology needs to be aware of.

Tetanic Contraction

When more than one activation is given and the interval between activations is within the time of the twitch contraction, summation occurs. That is, force will begin to rise again before relaxation is complete, like adding subsequent twitch contractions to what is already there. If oscillations of force are evident during repetitive activation, then this contraction is referred to as an incompletely fused tetanic contraction (Figure 5-11). If no oscillation of force is detected with each activation, then it is a completely fused tetanic contraction (Figure 5-12). The amount of relaxation between sequential activations depends on several factors: fibre-type, species, temperature, and sarcomere length.

Incompletely Fused Tetanic Contractions

The relationship between frequency of activation and active force is shown in Figure 5-13. When a muscle is activated at a very low frequency, independent twitch contractions will result. When sequential activations are delivered closer together, eventually an activation will arrive before complete relaxation has occurred. Now fusion occurs; first incomplete then complete as the frequency of activation increases. As frequency of activation increases, the average myoplasmic [Ca²⁺] will increase. With higher myoplasmic [Ca²⁺] active force will be higher, according to the force-[Ca²⁺] relationship (see Figure 5-14).

Completely Fused Tetanic Contractions

When sequential activations occur with a short interval, such that no relaxation is permitted between activations, the contraction is called a completely fused tetanic contraction. This complete fusion typically occurs near maximal active force.

Dynamic Contractions

Muscle contraction is a process that is triggered by binding of Ca²⁺ to troponin. The amount of Ca²⁺ that binds to troponin depends on motor unit recruitment (how many motor units are activated) and rate coding (frequency of activation of each motor unit). The consequence of muscle contraction is one of the following: shortening, lengthening, no change in length or stretch-shortening or shortening-stretch. One of the interesting and common types of contraction is the stretch-shortening contraction (Komi & Nicol, 2000). This is also known as a ballistic contraction where motion in one direction is slowed then reversed by contraction of the agonist for the shortening motion. For example, we often jump with a stretch-shortening contraction of our quadriceps muscles. The jump motion is preceded by a drop. We contract our quadriceps muscles to slow the drop, which is achieved with lengthening of these muscles and activate them more to accelerate upwards which requires shortening of the quadriceps muscles.

Fundamental Contractile Properties of Skeletal Muscle

The force of skeletal muscle contraction can be considered to be modulated by several fundamental factors: calcium concentration or frequency of activation, sarcomere length, and velocity of shortening. Each of these fundamental properties of muscle will be described here. In addition, the force response is dependent on the history of activation. Potentiation and fatigue, resulting from prior activation, are presented in the Chapter on “Repetitive Muscle Activation” (see Chapter 12).

Force-Frequency Relationship

Individual twitch contractions have an active force that is typically 10-30% of the maximal active force obtained with a completely fused tetanic contraction. Keeping in mind that muscles are activated by action potentials on motor nerves, the frequency of activation of a motor unit depends on the frequency of activation on the corresponding motor neuron. Frequency is the inverse of interval between sequential activations. Typically, human motor units are activated initially at about 8 Hz, and a brief contraction may have a train of 6-20 action potentials. Frequency of activation is often presented as an average because the actual interval between activations varies somewhat from one interval to the next.

As intensity of contraction increases, the frequency of activation increases, up to 60 to 80 Hz for sustained frequency. However, there is sometimes a higher frequency for the initial two or three activations for ballistic contractions. Higher frequency means more fusion and higher active force. Figure 5-13 shows the relationship between frequency of activation and active force for a maximally activated whole muscle of mixed fibre-type composition. Typically, a slow-twitch motor unit will have fusion at a lower frequency; a completely fused contraction will occur at a lower frequency. A fast-twitch motor unit will require a higher frequency of activation for complete fusion. The relationship between active force and frequency of activation is shifted to the left for slow-twitch motor units and to the right for fast-twitch motor units. Since slow-twitch motor units are typically smaller than fast-twitch motor units, the peak active force for slow-twitch motor units will be less than peak active force for fast-twitch motor units.

The frequency of activation will determine the average [Ca²⁺] in the myoplasm during the contraction. This concentration dictates the amount of binding to troponin C. The binding of Ca²⁺ to troponin C determines the number of cross-bridges that are cycling. Therefore, the force-frequency relationship is closely linked to the force-Ca²⁺ relationship. The relationship between frequency of activation and force is a sigmoidal relationship as seen in Figure 5-14.

Force-Velocity and Power–Velocity Relationships

The relationship between active force and length described above relates entirely to isometric contractions. When the muscle length is allowed to change during the contraction, the force exerted by individual cross-bridges will change, depending on whether length is increasing or decreasing. The force-velocity relationship describes the decrease in active force as the rate of shortening increases (see Figure 5-16). This relationship shows that as velocity of shortening increases, the force exerted decreases. The relationship is curved, and is described by the following hyperbolic equation:

(P + a) (v + b) = b (Po + a) = constantequation 5-1

where P is force, v is velocity of shortening, Po is isometric force, a and b are constants. This equation can be rearranged to the following (MacIntosh, Herzog, Suter, Wiley, & Sokolosky, 1993):

P= [b (Po + a) ( v+ b)^-1] – a equation 5-2

 

 

The curvature of the force-velocity relationship is dependent on temperature, fatigue, and fibre-type composition. The ratio of a:Po from the above equation defines the curvature. The smaller the value of this ratio, the greater is the curvature. The curvature is increased as temperature decreases. This is particularly important to understand the extreme curvatures of some published work on skeletal muscle (Hill, 1938). These measures were obtained in amphibian muscle at a temperature ranging from 0 to 25C, and have an a:Po ratio near 0.22. More physiological assessments of human muscle, in vivo, have yielded less curvature (a:Po =0.22 to 0.48) (Wilkie, 1950) to little or no curvature (MacIntosh et al., 1993). Fatigue can apparently have varied effects on the force-velocity relationship, and it is not clear why these differences have been observed. Some reports of the impact of fatigue on the force-velocity relationship indicate greater curvature (De Ruiter, Jones, Sargeant, & De Haan, 1999) while other reports show decreased curvature (Andrea N. Devrome & MacIntosh, 2018). Additional work is clearly needed to understand these differences. One thing is clear, the persistent changes observed in recovery are minimal with respect to the curvature. When mammalian muscle recovers from fatigue, low-frequency fatigue persists but the curvature of the force-frequency relationship returns to the control value (A. N. Devrome & MacIntosh, 2007).

Slow-twitch fibres have greater curvature in their force-velocity relationship than do fast-twitch fibres. This probably relates to the mechanism for the curvature described below. Combining fast and slow-twitch fibres in the same muscle accentuates the curvature. This is evident in figure 5-17 below, which shows 5 theoretical muscles with varying fibre-type composition (30-70% fast-twitch).

Figure 5-20 EMG-cadence relationship at 4 power outputs for an individual. This figure shows the relationship between magnitude of EMG (quantified as root mean square) for an average of 7 muscles involved in cycling at a variety of cadences at each of 4 power outputs from lowest line to upper line representing 100 W, 200 W, 300 W and 400 W. The data show that muscle activation is minimal at a unique cadence for each power output. The optimal cadence increases as power output increases. These data are from a single subject in the study described in the paper by MacIntosh and colleagues (2000).

Figure 5-21 In vivo force-length relationship of the medial gastrocnemius muscle. Active force is shown vs fascicle length. Individual contractions are illustrated by the blue dots. The line represents a straight line fit to the data.

In the discussion of the paper, the author presents an estimate of the sarcomere length of the medial and lateral gastrocnemius muscles over the range of measured active force. It is assumed that the medial gastrocnemius muscle fibres have 17,600 sarcomeres in series and by dividing the measured fascicle length by the number of sarcomeres, the sarcomere length can be estimated. It is estimated that the sarcomeres range from 1.4 to 2.2 µm. This seems like a short sarcomere length for this muscle, considering the filament lengths of human muscle (see Figure 5-23 above). It seems unlikely that any active force could be generated at a sarcomere length below 1.6 µm. Most muscle physiologists would argue that the muscle should be at or near the plateau of the force-length relationship during maximal activation. The author argues that this range of sarcomere lengths is reasonable because the muscles would normally be used in submaximal contractions, and this would result in less stretch of the tendon and therefore a longer sarcomere length. The plateau of the force-length relationship should be 2.6-2.8 µm.

Fukunaga et al (2001) used a similar assumption to estimate that sarcomere length in the medial gastrocnemius muscle during walking was in the range of 2.75-2.92 µm. It would have been nice to know the resting length of the fascicle in this study.

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Summary

The structure of muscle, presented in Chapter 4 relates well to the function of muscle presented here in Chapter 5. Muscle is organized into motor units, groups of cells that are activated together with a series of action potentials on a given axon. When an action potential arrives at the nerve terminal, neuromuscular transmission allows activation of all of the muscle fibres associated with that motor unit. Excitation-contraction coupling is the process that turns the neural signal into a contraction. The action potential is transmitted along the sarcolemma and into the transverse tubules where the dihydropyridine receptors detect the voltage change. The dihydropyridine receptors signal the ryanodine receptors to open and allow Ca²⁺ to flow out of the terminal cisternae into the cytoplasm. Ca²⁺ initiates the contraction, which can be fixed-end or dynamic (shortening or lengthening The magnitude of response is dependent on many factors, including the concentration of Ca²⁺ achieved with the activation. Sensitivity to Ca²⁺ can also be altered. The energy for muscle contraction comes from adenosine triphosphate a universal biological energy source. Fundamental properties of muscle dictate the nature of the contractile response. These properties include the force-length relationship, the force-frequency relationship, the force-velocity relationship and the power-velocity relationship.

Review Questions:

1. What is the name of the Ca²⁺-binding protein on the thin filaments that must bind Ca²⁺ to allow actin-myosin interaction?

a. Tropomyosin

b. Calmodulin

c. Parvalbumin

d. Troponin C

e. Troponin I

 

2. Where does Ca²⁺ come from on activation of a myocyte and where does it go to allow relaxation?

 

a. Extracellular space

b. Capillary

c. Sarcoplasmic reticulum

d. Mitochondria

e. All of the above

 

3. What direction of pumping is achieved by the sodium-potassium pump?

 

a. Sodium and Potassium into the cell

b. Sodium out of the cell and potassium into the cell

c. Sodium and Potassium out of the cell

d. Potassium into the cell

 

4. What does the lower case “p” mean in front of “H” or “Ca²⁺”?

 

a. Negative log

b.Natural log

c. Log function of

d. None of the above

 

5. What is the force exerted by muscle when the velocity of shortening is fastest?

 

a. Maximum isometric force

b.Half of maximal isometric force

c. 1/3 of maximal isometric force

d. Zero

 

6. What is the velocity at peak power output?

a. Optimal velocity

b. Zero

c. Maximal velocity

 

7. What circumstance allows the highest isometric force at a sarcomere length of 2.6 m?

a. Overlap of filaments is minimal

b. Overlap of filaments is optimal

c. Muscle cross-sectional area is the greatest at this length

d. More Ca²⁺ is released for each action potential

 

8. What happens to optimal length with submaximal activation of skeletal muscle?

a. Optimal length remains constant

b. Optimal length occurs at shorter sarcomere length

c. Optimal length occurs at longer sarcomere length

d. Optimal length is lost (force is same at all lengths)

 

9. What protein binds Ca²⁺ and activates myosin light chain kinase?

a. Troponin C

b. Parvalbumin

c. Troponin I

d. Calmodulin

 

10. What property of muscle allows force to be higher as frequency of stimulation increases?

a. Force-velocity relationship

b. Summation

c. Force-length relationship

d. All the above

Answers to multiple-choice questions:

1. d; 2. c; 3. b; 4. a; 5. d; 6. a; 7. b; 8. c; 9. d; 10. b

Exercises or Topics for Discussion:

• What are the factors that could allow two individuals with the same maximal isometric force when one of them was 2 m in height and the other was 1.6 m in height?
• How would you determine the force-length relationship for the elbow flexor muscles?
• Describe the sequence of events in excitation-contraction coupling.
• What factors would be important in determining how fast a catapult could launch a pumpkin and how does this relate to muscle function?

References

Balnave, C. D., & Allen, D. G. (1995). Intracellular calcium and force in single mouse muscle fibres following repeated contractions with stretch. Journal of Physiology, 488, 25-36.

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