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Is the heart more relaxed when stretched or contracted, and how does it affect cross-bridge interactions?

Is the heart more relaxed when stretched or contracted, and how does it affect cross-bridge interactions?


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In the heart, are stretched muscles during the diastole more relaxed or are the contracted muscles more relaxed? Depending on the answer, are there then more cross-bridge interactions in cardiac muscle cells when the heart is stretched or contracted?


The muscular portion of the heart is comprised of cardiac myocytes, elongated cells filled with bundles of actin and myosin called sarcomeres. These cells are similar in many respects to skeletal muscles, but are shorter, have only one nucleus, and slightly different isoforms (versions) of the proteins involved. The purpose of this cell, like the skeletal muscle cell, is contraction, or shortening on activation.

This image of cardiac muscle cells shows how full they are with long bands of proteins (proteins stain pink).

Because the heart is a muscular chamber, instead of simply a band of muscle (like the bicep), the relevant dimension for the organ is volume instead of length. Where your bicep gets shorter when it contracts (and pulls your forearm toward your upper arm, bending at the elbow joint), when your heart muscle contracts, it twists and squeezes against the fibrous part of the organ, decreasing the volume of the chamber.

Since there is no air in a healthy live heart, when the heart contracts, reducing the volume of the container, the blood is forced out of the heart (ejection) through whatever opening is available. This is called systole. When the heart relaxes, the volume of the container increases, and blood enters the container through whatever opening is available. this is called diastole.

Now, how is this related to cross-bridge interactions?

The mechanism for contraction itself, in both skeletal and cardiac muscle, is cross-bridge cycling. Those pink bundles of actin, myosin, and associated proteins in the picture above form bonds, change conformation, break bonds, change conformation, and form new bonds:

This cross-bridge cycling occurs during contraction when $Ca^{++}$ enters the cell as part of the cardiac action potential. Relaxation occurs when $Ca^{++}$ concentrations decrease, through the action of the $Ca^{++}$-ATPase, causing cross bridge interactions to decrease.


Muscle Fiber Contraction and Relaxation

The sequence of events that result in the contraction of an individual muscle fiber begins with a signal—the neurotransmitter, ACh—from the motor neuron innervating that fiber. The local membrane of the fiber will depolarize as positively charged sodium ions (Na + ) enter, triggering an action potential that spreads to the rest of the membrane will depolarize, including the T-tubules. This triggers the release of calcium ions (Ca ++ ) from storage in the sarcoplasmic reticulum (SR). The Ca ++ then initiates contraction, which is sustained by ATP ([link]). As long as Ca ++ ions remain in the sarcoplasm to bind to troponin, which keeps the actin-binding sites “unshielded,” and as long as ATP is available to drive the cross-bridge cycling and the pulling of actin strands by myosin, the muscle fiber will continue to shorten to an anatomical limit.


Muscle contraction usually stops when signaling from the motor neuron ends, which repolarizes the sarcolemma and T-tubules, and closes the voltage-gated calcium channels in the SR. Ca ++ ions are then pumped back into the SR, which causes the tropomyosin to reshield (or re-cover) the binding sites on the actin strands. A muscle also can stop contracting when it runs out of ATP and becomes fatigued ([link]).



The release of calcium ions initiates muscle contractions. Watch this video to learn more about the role of calcium. (a) What are “T-tubules” and what is their role? (b) Please describe how actin-binding sites are made available for cross-bridging with myosin heads during contraction.

The molecular events of muscle fiber shortening occur within the fiber’s sarcomeres (see [link]). The contraction of a striated muscle fiber occurs as the sarcomeres, linearly arranged within myofibrils, shorten as myosin heads pull on the actin filaments.

The region where thick and thin filaments overlap has a dense appearance, as there is little space between the filaments. This zone where thin and thick filaments overlap is very important to muscle contraction, as it is the site where filament movement starts. Thin filaments, anchored at their ends by the Z-discs, do not extend completely into the central region that only contains thick filaments, anchored at their bases at a spot called the M-line. A myofibril is composed of many sarcomeres running along its length thus, myofibrils and muscle cells contract as the sarcomeres contract.


THE CONTRACTILE MECHANISM

In the intact body, the process of smooth muscle cell contraction is regulated principally by receptor and mechanical (stretch) activation of the contractile proteins myosin and actin. A change in membrane potential, brought on by the firing of action potentials or by activation of stretch-dependent ion channels in the plasma membrane, can also trigger contraction. For contraction to occur, myosin light chain kinase (MLC kinase) must phosphorylate the 20-kDa light chain of myosin, enabling the molecular interaction of myosin with actin. Energy released from ATP by myosin ATPase activity results in the cycling of the myosin cross-bridges with actin for contraction. Thus contractile activity in smooth muscle is determined primarily by the phosphorylation state of the light chain of myosin—a highly regulated process. In some smooth muscle cells, the phosphorylation of the light chain of myosin is maintained at a low level in the absence of external stimuli (i.e., no receptor or mechanical activation). This activity results in what is known as smooth muscle tone and its intensity can be varied.


Abstract

Cardiac myosin–binding protein-C (cMyBP-C) is a thick filament-associated protein that seems to contribute to the regulation of cardiac contraction through interactions with either myosin or actin or both. Several studies over the past several years have suggested that the interactions of cardiac myosin–binding protein-C with its binding partners vary with its phosphorylation state, binding predominantly to myosin when dephosphorylated and to actin when it is phosphorylated by protein kinase A or other kinases. Here, we summarize evidence suggesting that phosphorylation of cardiac myosin binding protein-C is a key regulator of the kinetics and amplitude of cardiac contraction during β-adrenergic stimulation and increased stimulus frequency. We propose a model for these effects via a phosphorylation-dependent regulation of the kinetics and extent of cooperative recruitment of cross bridges to the thin filament: phosphorylation of cardiac myosin binding protein-C accelerates cross bridge binding to actin, thereby accelerating recruitment and increasing the amplitude of the cardiac twitch. In contrast, enhanced lusitropy as a result of phosphorylation seems to be caused by a direct effect of phosphorylation to accelerate cross-bridge detachment rate. Depression or elimination of one or both of these processes in a disease, such as end-stage heart failure, seems to contribute to the systolic and diastolic dysfunction that characterizes the disease.

Cardiac myosin–binding protein-C (cMyBP-C) is one of a small family of homologous proteins that bind to myosin in mammalian-striated muscles (Figure 1). After its first description in skeletal muscle by Offer and colleagues, 2 MyBP-C (or C-protein as it was first named) was thought to play a principally structural role in the assembly and stabilization of the sarcomere, although early work by Moos suggested there were conditions under which C-protein modified the function of myosin in solution, in either the presence or absence of actin. 3 Subsequent work by Hartzell 4 showed in the amphibian heart that the phosphorylation state of C-protein varied with the infusion of a membrane receptor agonist (acetylcholine), an observation that led to a series of structural, biochemical, and functional studies of the protein. 5–8 cMyBP-C was found to be phosphorylated at specific residues by protein kinase A (PKA) and calcium calmodulin kinase 2 delta (CaMK2δ) 6 and was also reversibly phosphorylated in vivo when β-adrenergic agonists were applied to the mammalian heart. 9 The findings that biochemical extraction of cMyBP-C from the myofibril had no effect on the stability of the sarcomere 7 and that genetic ablation of cMyBP-C in mice caused no abnormalities in sarcomere assembly 10 led to the conclusion that cMyBP-C is not a structural protein, at least not in the strictest sense. In recent years, the picture that has emerged is one in which cMyBP-C is a key determinant of the speed and force of cardiac contraction, a conclusion drawn from alterations in contractility that have been observed as a consequence of phosphorylation, ablation, or mutation of the protein.

Figure 1. Salient features of cardiac myosin-binding protein-C. A, An electron micrograph of a cardiac sarcomere showing the transverse stripes corresponding to the alignment of cardiac myosin binding protein-C (cMyBP-C) in each half-sarcomere. 1 cMyBP-C was visualized by infusion of an N-terminal antibody before fixation. B, cMyBP-C showing its subunit structure and featuring the protein kinase A (PKA) phosphorylatable serines in the regulatory domain, that is, M-domain between subunits C1 and C2. cMyBP-C is a phospho-protein that is localized to 9 stripes (the C zone) in each half sarcomere. The stripes are 42 nm apart, corresponding to every third myosin crown.

CMyBP-C Regulates the Kinetics of Force Development in Myocardium

CMyBP-C as a Regulator of Contraction

The overarching conceptual framework for this review is that cMyBP-C binds to myosin or actin or both and thereby regulates the probability of cross-bridge interaction with actin, which in turn controls the rates of force development and relaxation in living muscle. In this regard, there is evidence (reviewed below) that dephosphorylated cMyBP-C preferentially binds to myosin and in so doing restricts spatial mobility of myosin and reduces the probability of myosin binding to actin. This MyBP-C–mediated depression of contractility is relieved by genetic ablation of MYBPC3 (the gene encoding cMyBP-C) 10 or phosphorylation of cMyBP-C by PKA, CaMK2δ, and possibly other kinases. 6,11–14 cMyBP-C also binds to actin, which seems to have activating effects on the thin filament (below), leading to the idea that phosphorylation increases contractility by shifting the balance of cMyBP-C from myosin to actin. Such mechanisms would ensure that power generation and the efficiency of myocardial contraction are optimal in an individual at rest, but provides considerable contractile reserve for enhanced function when the heart is stressed by increases in circulatory load or neuro-humoral tone. As an example of the potential importance of these regulatory processes, failure of these mechanisms caused by depressed adrenergic signaling in heart failure most likely contributes to the reduced contractility of myocardium that is the hallmark of the disease. In contrast, hypertrophic cardiomyopathy mutations in cMyBP-C that are associated with hypercontractility even in an individual at rest presumably induce hypercontractility by disrupting the interactions of cMyBP-C with myosin or increasing its binding to actin or both.

Evidence for MyBP-C-Mediated Regulation of Cross-Bridge Cycling Kinetics

Early studies of possible roles of MyBP-C in muscle contraction found that biochemical extraction of MyBP-C from skinned skeletal or cardiac muscle increased the force developed at Ca 2+ concentrations that evoked forces less than maximal, that is, increased the Ca 2+ sensitivity of force, and also increased the velocity of unloaded shortening at submaximal [Ca] 2+ . 7 Both results suggested that MyBP-C depressed contraction in muscle, a conclusion that was reinforced by reversal of these effects of extraction when the muscle preparations were reconstituted with MyBP-C.

A limitation of experiments involving biochemical extraction of cMyBP-C from permeabilized muscle fibers is the inability to determine the effects of stoichiometric depletion of the protein or the effects of depletion on myocardial function in vivo. The first cMyBP-C knockout mouse was developed to address the need for such data. Rather than causing disruption of sarcomere assembly, homozygous ablation of the MYBPC3 gene resulted in a series of phenotypes, such as septal hypertrophy, chamber dilation, accelerated rate of rise of left-ventricular pressure, and slowed relaxation, 10 all of which are consistent with changes reported in many cases of inherited hypertrophic cardiomyopathy. 15–17

Extension of these studies to permeabilized preparations of cMyBP-C null myocardium showed that ablation increased the rate of rise of force at submaximal [Ca] 2+ , 18,19 a phenomenon that accounts for the accelerated kinetics of pressure development in null hearts, but had no effect on the kinetics of force development at saturating [Ca] 2+ . In contrast to the slowed myocardial relaxation (and resulting diastolic dysfunction) in null hearts in vivo, 20 relaxation of permeabilized null myocardium was accelerated compared with wild-type. 18 This finding has been corroborated by data derived from a multicellular engineered cardiac tissue preparation incorporating neonatal cMyBP-C null cardiomyocytes, which exhibited an acceleration of the relaxation phase of the twitch. 21 This suggests that slowed relaxation in vivo is related to alterations in Ca 2+ handling as a result of functional remodeling of the heart as part of the compensatory response to ablation of cMyBP-C. 12 Consistent with this idea, the intracellular Ca 2+ transient is substantively altered in intact single cardiomyocytes from cMyBP-C null myocardium, that is, the amplitude is reduced and the kinetics of rise and fall of the transient are slowed. 22 Under these circumstances, the rate of relaxation of the twitch seems to be determined mainly by the rate of decay of the Ca 2+ transient. This conclusion is consistent with the finding by David Yue and colleagues that most of the time-course of relaxation of force during the cardiac twitch follows the steady-state relationship between force and [Ca] 2+ determined in the same muscles. 23 Nevertheless, the kinetics of the calcium transient did not differ in null versus wild-type engineered cardiac preparation, which reinforces the idea that ablation per se of cMyBP-C accelerates relaxation.

Regulation of Cross-Bridge Cycling by PKA Phosphorylation of MyBP-C

Several earlier studies reported that cMyBP-C is reversibly phosphorylated by PKA or CaMK2δ, indicating a regulatory role for cMyBP-C as an element of β-adrenergic stimulation of the heart. 6 Consistent with this idea, infusion of PKA in permeabilized cardiac muscle from murine hearts accelerates the rate of rise of force at submaximal [Ca] 2+ but has no effect on the kinetics of force development at saturating [Ca] 2+ . These effects (and the lack of effect at saturating [Ca]) 2+ are similar to the effects caused by ablation of cMyBP-C. In mouse models expressinging non-PKA-phosphorylatable cMyBP-C, no acceleration in kinetics of force is measured during exposure to either PKA in skinned myocardium or dobutamine in living myocardium. 12 Thus, the mechanism underlying the effects of PKA mimics the contractile effects caused by ablation, perhaps reducing or eliminating regulatory interactions of cMyBP-C with myosin or with actin. PKA phosphorylates both cMyBP-C and cardiac troponin I in the cardiac myofibril, but the effects on kinetics are because of phosphorylation of cMyBP-C because the effects are observed in myocardium expressing nonphosphorylatable TnI but are not observed in myocardium expressing native TnI and nonphosphorylatable cMyBP-C. 12 Thus, phosphorylation of cMyBP-C accelerates force development in isolated muscle and would be expected to contribute to the acceleration of pressure development in the intact heart during adrenergic stimulation, which was also reported by Tong et al. 12

Three highly conserved, physiologically relevant phosphorylation sites were identified by Gautel within the N-terminus region between C1 and C2, referred to as the MyBP-C motif or the M-domain. 6 Three serine (Ser) residues (mouse: Ser-273, -282, and -302 human: Ser-275, -284, and -304) comprise the primary PKA substrates (Figure 1) and are thus implicated in mediating the cMyBP-C response to β1 adrenergic stimulation. The initial studies by Gautel suggested nonequivalency of the phosphorylation sites based on mutagenesis data, indicating an essential function for Ser-282 phosphorylation for subsequent phosphorylations of Ser-273 and Ser-302. 6 Although recent data suggest that PKA phosphorylation of Ser-282 may not be necessary for phosphorylation of the flanking sites, 24 functional data from transgenic models expressing an array of phosphomimetic and nonphosphorylatable combinations at these residues indicates that the individual sites do not exert equal effects on cross-bridge kinetics or force production. 25–27 Thus, each site seems to exert unique, albeit subtly different, effects on contractile and morphological phenotypes. 26

Although PKA readily phosphorylates all 3 serine residues in the M-domain, additional kinases including CaMK2δ, protein kinase C, protein kinase D, and perhaps ribosomal S6 kinase, have been shown to selectively phosphorylate a subset of these sites. 28 Work by Gautel 6 suggested that residue Ser-282 in mouse cMyBP-C is readily phosphorylated by CaMK2δ, whereas subsequent work has shown that CaMK2δ phosphorylates Ser-282 only at high [Ca] 2+ but Ser-302 at low [Ca] 2+ . Protein kinase C phosphorylation of cMyBP-C has been shown in human myocardium 29 and in mouse hearts to selectively target Ser-273 and Ser-302. 30 Phosphomimetic substitution at these protein kinase C sites in the absence of Ser-282 phosphorylation leads to severe cardiac hypertrophy, whereas a nonphosphorylatable Ser-273 and Ser-302 model with or without a concurrent phosphomimetic substitution at Ser-282 did not manifest any significant changes. There is need for additional work to elucidate the role(s) of protein kinase C and potentially other Gq protein-coupled receptor-activated kinases, such as protein kinase D and ribosomal S6 kinase, in health and disease, but in any case, the work cited above suggests a role for cMyBP-C in mediating cardiac inotropic effects in response to α1-adrenergic stimulation.

In normal hearts, cMyBP-C may be highly phosphorylated at baseline, in some studies approaching 90% in mouse hearts, with a fairly even distribution among the mono-, di-, and triphosphorylated forms. 25 The possible functional implications of variable phosphorylation have been illuminated using an in vitro motility assay measuring the rate of movement of labeled thin filaments over bound myosin in the presence of C0-C3 fragments of cMyBP-C mutated at the 3 serine sites to either be phospho-mimetic or phospho-ablated. 31 The relationship between sliding velocity (reflecting cross-bridge kinetics) and the extent of cMyBP-C phosphorylation is striking, implying a modulation capability based on the degree of phosphorylation, rather than a simple full-on/full-off response. Therefore, the mix of kinases, each associated with their unique physiological responses, as well as the identity of the serine(s) that confer functional effects when phosphorylated, are critical variables in the context of developing possible therapeutic interventions designed to improve function by targeting kinase activities or phospho-residues. The development by Sadyappan of highly specific phosphoserine antibodies to each of the 3 phosphoserines (Ser-272, Ser-283, and Ser-302) in mouse cMyBP-C provides a powerful set of tools with which to optimize the selection of therapeutic targets. 32

Model for the Regulation of the Kinetics of Force Development and Relaxation by cMyBP-C

Critical Constraint on Possible Mechanisms of Regulation by cMyBP-C

Consideration of the possible mechanisms by which phosphorylation of cMyBP-C influences contraction kinetics and myocardial force must take into account the observation that phosphorylation does not accelerate the rate of rise of force in skinned myocardium that is maximally activated with Ca 2+ , 11 as shown in Figure 2. The lack of effect of phosphorylation implies that the rate of cross-bridge cycling is indeed maximal at saturating Ca 2+ , which places constraints on possible mechanisms by which phosphorylation accelerates kinetics at submaximal Ca 2+ concentrations. Most notably, it seems unlikely that phosphorylation has its effects by increasing the proximity of cross bridges to actin, suggested previously, 33,34 because such a mechanism should accelerate contraction kinetics even at maximal activation by increasing the probability of binding to actin. Thus, the previous observations of an apparent transfer of molecular mass from thick filaments to thin, inferred from greater equatorial I1,1/I1,0 intensity ratios from x-ray diffraction patterns recorded from phospho-mimetic cMyBP-C or cMyBP-C ablated myocardium, 34,35 could represent a more subtle change in myosin structure because of these interventions. Because the changes in intensity ratios were observed in relaxed myocardium, the transfer of mass from one diffracting plane (thick filaments only in the 1,0 plane) to another (thick and thin filaments in the 1,1 plane) cannot be a straightforward result of increased cross-bridge binding, thus eliminating the possibility of a trivial explanation for these results. Instead, a cMyBP-C phosphorylation-induced structural change in myosin inferred from the change in equatorial intensity ratios seems to be the cause rather than a result of increased cross-bridge binding to actin and the increased rate of force development under these conditions.

Figure 2. Effects of ablation or phosphorylation of cardiac myosin binding protein-C (cMyBP-C) on the kinetics of force development and relaxation. The rates of delayed force development (rate constant kdf) and relaxation (krel) were measured during the force transient resulting from sudden stretch of skinned myocardium activated at different Ca 2+ concentrations to develop forces of ≈25%, 50%, and 100% of maximum. 11 A, kdf in wild-type increased nearly 4-fold when activation was increased from 25% to 100% of maximum homozygous knockout of cMyBP-C accelerated the rate of force development during submaximal activations but not at maximal activation. B, Protein kinase A (PKA) phosphorylation of cMyBP-C in wild-type myocardium increased kdf during submaximal activations, but there was no effect on kdf at maximal activation. C, Knockout of cMyBP-C increased the rate of relaxation (krel) at submaximal but not at maximal activation. D, Similar to knock of cMyBP-C, PKA phosphorylation of cMyBP-C accelerated krel in wild-type myocardium at submaximal but not at maximal activation. Thus, phosphorylation of cMyBP-C had no effect on cross-bridge cycling kinetics at maximal activation but accelerated the rates of force development and relaxation during submaximal activation. These effects were as a result of phosphorylation of cMyBP-C and not cardiac troponin I (cTnI) because wild-type myocardium expressing nonphosphorylatable TnI (TnIala2) exhibited accelerated rates of force development and relaxation.

Plausible Mechanisms of Regulation of the Cross-Bridge Cycle via cMyBP-C

Although the detailed mechanism by which phosphorylation of cMyBP-C accelerates contraction is not yet understood, consideration of current models of the regulation of contraction by myofibrillar proteins provides useful clues and a framework for further mechanistic studies. Models of regulation are constrained to explain the activation dependence of the rate constant of force development (kfd) in permeabilized myocardium after either photo-generation of Ca 2+ from caged Ca 2+ (yielding the rate constant kCa), photo-generation of adenosine diphosphate (ADP) from caged ADP (yielding kADP), or a release/restretch protocol during steady activation at varying Ca 2+ concentrations (yielding ktr). In myocardium, there is an ≈10-fold acceleration of kfd as [Ca] 2+ is increased from threshold levels for force generation to maximal activation. 36,37

There are 3 general classes of regulatory mechanisms that could be invoked to explain the variation in kfd as a function of [Ca] 2+ , each of which could plausibly be modulated by the phosphorylation status of cMyBP-C and none of which has yet been excluded as a possibility. In one current model of regulation, this activation dependence was simulated by including [Ca] 2+ as a reactant in the force generating transition, 38 which would result in accelerated force development as [Ca] 2+ is increased. A second possibility is that kinetic transitions in the cross-bridge interaction cycle, notably the release of the products of ATP hydrolysis (Pi and ADP), are directly regulated as functions of thin filament activation caused by Ca 2+ binding to the troponin complex. Such a mechanism would presumably involve allosteric modulation of these transitions as a consequence of changes in conformation of the thin filament regulatory strand as the amount of Ca 2+ bound to troponin increases from threshold to saturating for force development. At saturating Ca 2+ , the kinetics of cross-bridge turnover would presumably approach the intrinsic kinetics of the limiting step in the cross-bridge cycle, that is, the rate of ADP release. A third possibility is that the rate of force development is slowed at low Ca 2+ concentrations because of the time taken for the cooperative recruitment of cross bridges to the thin filament. 39,40 Such recruitment would be triggered by the initial binding of Ca 2+ to troponin and is characterized by the progressive spread of cross-bridge binding away from the troponin with Ca 2+ bound. This mechanism would be most pronounced at low [Ca] 2+ because relatively few troponins would have Ca 2+ bound, leaving extended regions of thin filament available for cooperative activation the mechanism would presumably not be operable at saturating Ca 2+ because the thin filament would be fully activated by Ca 2+ , leaving no regions of the thin filament available for cooperative recruitment of cross bridges. Thus, at high [Ca] 2+ , the kinetics of force development would approach the fundamental rate of cross-bridge cycling.

Although all 3 of these mechanisms could conceivably contribute to the regulation of the kinetics of contraction, it is not presently known which of the 3 are involved, which of the 3 are predominant, or the conditions that may favor one versus another. Of course, these 3 mechanisms are not mutually exclusive—for example, any effect of variations in [Ca] 2+ to modulate cross-bridge cycling rates would be expected to modulate the rate of cooperative activation of the thin filament. Similarly, any effect of the phosphorylation status of cMyBP-C to modulate ≥1 of these mechanisms would be expected to influence any other mechanisms that contribute to the regulation of contraction.

Interactions of cMyBP-C With Myosin and Actin

The above discussion begs the identity of the molecular interactions that mediate the regulation of contraction by cMyBP-C. Of course, cMyBP-C has from the time of its discovery been thought to bind to myosin, an interaction that is weakened or eliminated by phosphorylation of serines within the cMyBP-C motif, or M-domain. 6 More recent evidence obtained principally in simplified systems of proteins in solution but also using a yeast 2-hybrid approach suggest the possibility that cMyBP-C also binds actin. 41,42 Such binding has been associated with the activation of regulated motility assays in the absence of added Ca 2+ , 43 the slowing of sliding velocity in motility assays as thin filaments slide into the region of the thick filament (C-zone) where cMyBP-C is bound, 44,45 and the displacement of tropomyosin within the thin filament toward positions similar to Ca 2+ activation. 46 Although the binding of cMyBP-C to actin is relatively weak, 41,47 the affinity is in a range (a few micromolar) that is well suited to regulation in which phosphorylation modulates the interaction of cMyBP-C with its binding partners. Supporting this idea, it is evident that cMyBP-C alters the torsional dynamics of thin filaments in solution, an effect that varies with phosphorylation state of cMyBP-C. 48

The idea that cMyBP-C binds to both the thick and thin filaments, depending on the phosphorylation state of the protein, was first proposed by Moos 3 and confirmed in several recent studies. 42,49,50 As suggested by Gautel, 51 phosphorylation of cMyBP-C would be expected to disrupt its binding to myosin, thereby increasing the rate of force development by increasing the probability of myosin binding to actin. At the same time, the now-phosphorylated cMyBP-C could bind to actin and further activate the thin filament. In this regard, Craig 46 showed in 3D reconstructions of cardiac thin filaments that an N-terminal domain of cMyBP-C displaced tropomyosin to a position corresponding to an activated, Ca 2+ -bound thin filament. Though not as pronounced as the effects of unphosphorylated cMyBP-C, infusion of the phosphorylated protein clearly displaces tropomyosin toward an activated position, which would presumably bias the filament toward the activated state. Thus, cMyBP-C would bind preferentially to myosin when unphosphorylated, which would depress activation caused by a structural constraint of cross bridges, and to the thin filament when phosphorylated, which would enhance activation caused by relief of the structural constraint of cross bridges and also increased activation of the thin filament as a consequence of cMyBP-C binding to actin.

The identity of binding partners involved in the regulation of contraction by post-translational modification of cMyBP-C has emerged as one of the most pressing issues today in myocardial biology. The importance of this information derives from our understanding that these interactions mediate cMyBP-C-phosphorylation–dependent effects on contraction, for example, adrenergic inotropy. Knowledge of the specific mechanism(s) of these effects would provide specific targets for development of therapeutics for treatment of myocardial dysfunction caused by reduced contractility, as in heart failure, or hypercontractility, as in hypertrophic cardiomyopathies.

Proposed Role of cMyBP-C in the Regulation of Cooperative Recruitment of Cross Bridges to the Thin Filament

As described earlier, the binding of cross bridges to the partially activated thin filament is a highly cooperative process, particularly in cardiac muscle, which operates at submaximal levels of activation due largely to the short duration of the intracellular Ca 2+ transient that underlies the twitch. Cooperativity in the regulation of cardiac contraction kinetics has been described previously. 52,53 For example, the rate constant of force development can be accelerated by an order of magnitude at low, steady Ca 2+ concentrations by cooperatively activating the thin filament via infusion of N-ethylmaleimide-modified myosin subfragment 1, 36 a strong-binding, nonforce-generating derivative of myosin subfragment 1.

The activation dependence of cardiac contraction and the kinetics of force development has been modeled by Campbell as the effects of cooperative cross-bridge binding to actin to increase both the number of formed cross bridges and the amount of force that is generated. 39,40 This model is shown diagrammatically in Figure 3, with a detailed explanation of the model in the figure legend. The key feature of the model is that Ca 2+ binding to an isolated troponin activates the thin filament for initial binding of cross bridges to actin (Figure 4), but once a cross bridge binds, the activation state of the thin filament is greater than it would be because of the presence of bound Ca 2+ alone. 54–56 This enhancement of activation promotes the binding of cross bridges at a still greater distance from the Ca 2+ -bound troponin. This cooperative spread does not extend beyond a certain distance, for example, ±14 actin residues 57 because the activating effect of Ca 2+ decays with distance from Ca 2+ -bound troponin. In this model, the rate of force development is related not only to the rate of Pi release during the force-generating step but also the rate of propagation of cooperative cross-bridge recruitment away from the site of initial Ca 2+ binding (Table 1).

Table. Cooperative Activation of Cardiac Force Development

Figure 3. Modulation of cross-bridge cycling by phosphorylation of cardiac myosin binding protein-C (cMyBP-C). The diagram shows a plausible mechanism by which phosphorylation of cMyBP-C speeds the rate of force development (©Moss and Fitzsimons, 2010. Originally published in Journal of General Physiology. doi:10.1085/jgp.201010471). In the presence of Ca 2+ nucleotide-bound myosin (M·ADP·Pi) binds actin (A), which is followed by Pi release and force development as cross-bridges populate the primary force generating state (A-M·ADP). On release of ADP, the resulting rigor complex rapidly binds ATP, which is followed by dissociation of M·ATP from A, hydrolysis of ATP, and re-entry of M·ADP·Pi into the cycle. According to Campbell’s model of activation, 39 force-generating cross-bridges bound to the (A-M·ADP) cooperatively recruit near-neighbor cross-bridges to bind to actin, shown by the clock-wise loop on the left. 52 This cycle of recruitment may involve multiple iterations so that the time required to reach steady force, that is, a steady population of A-M·ADP cross-bridges, is determined principally by the time taken to complete the iterative recruitment process. In our modification of this model, cMyBP-C slows cooperative recruitment by placing a physical constraint on myosin, thereby reducing the probability of myosin binding to actin and slowing the cooperative spread of cross-bridge binding. Phosphorylation of cMyBP-C by protein kinase A (PKA), CaMK2δ, or other kinases relieves this constraint either by disrupting the interaction of cMyBP-C with myosin, thereby increasing the probability of myosin binding to actin or binding to the thin filament, thereby increasing its activation state and accelerating cross-bridge binding. Both of these mechanisms, either singly or together, would be expected to increase the rate of force development.

Figure 4. Maps of the cardiac thin filament showing the activating effects of Ca 2+ and strongly bound cross-bridges. The panels in this figure represent the state of activation of the thin filament (A) in the absence of Ca 2+ (B) when Ca 2+ binds to a single troponin (yellow structures), and (C) in response to the sequential cooperative binding of cross-bridges in response to Ca 2+ binding to troponin. Binding of Ca 2+ alone results in activation that is constrained with respect to amplitude and spread subsequent binding of one and then another cross-bridge increases the amplitude and spread of activation. We propose that phosphorylation of cardiac myosin binding protein-C (cMyBP-C) increases the rates of transition from the Ca 2+ activation envelope (shaded area) to the expanded envelope (dashed line) because of binding of 1 cross-bridge (rate constant k1) and then the further expanded envelope (dotted line) because binding of a second cross-bridge (k2).

We propose that phosphorylation of cMyBP-C accelerates the rate of force development by accelerating the rate of cooperative cross-bridge recruitment described by Campbell in his model. 39,40 This mechanism is shown diagrammatically in Figure 4 as an effect of phosphorylation to increase the rate constants (k1 and k2) governing the rates of transition to progressively higher and broader activation profiles around sites of Ca 2+ binding to troponin. The mechanism also accounts for the lack of effect of cMyBP-C phosphorylation on the kinetics of force development at saturating levels of Ca 2+ because at these levels, adjacent regions of the thin filament are already activated by Ca 2+ , and cooperative cross-bridge recruitment would be absent or much diminished compared with a partially activated thin filament.

The molecular mechanism by which phosphorylation of cMyBP-C would accelerate cooperative recruitment could involve an increased rate of cross-bridge binding to actin as a consequence of the disruption in binding of cMyBP-C to myosin. As discussed earlier, the mechanism may also involve an enhancement of thin filament activation caused by binding of phosphorylated cMyBP-C to actin, presumably as a result of a binding-induced displacement of tropomyosin. 46 Thus, inotropy involving phosphorylation of cMyBP-C may be mediated by increases in the rate of cross-bridge binding and the extent of spread of cooperative binding during a given [Ca] 2+ in transient. Graded effects on twitch amplitude and kinetics, for example, at low levels of β1-adrenergic stimulation, would in this model be caused by reduced phosphorylation of cMyBP-C. In such circumstances, the presence of partially phosphorylated or unphosphorylated cMyBP-C would slow the binding of nearby cross bridges and thereby slow the spread of cooperative cross-bridge recruitment. In this regard, cMyBP-C may be involved in signaling activation from the thin filament to the thick filament. 58

Can This Model Explain Physiological and Pathophysiological Phenomena?

The potential effect of the proposed model lies in its usefulness as a framework for explaining contractile phenomena. With respect to physiological phenomena, it is clear that cMyBP-C is phosphorylated during β-adrenergic stimulation 9 and also as a result of increased frequency of stimulation. 12 In the case of adrenergic stimulation, PKA phosphorylation of cMyBP-C would be expected to contribute to accelerated dP/dtmax and increased twitch force as a consequence of acceleration of cooperative cross-bridge recruitment to the thin filament. Similarly, the increase in twitch force as a function of stimulus frequency, that is, the Bowditch effect or treppe, would increase force as a result of CaMK2δ phosphorylation of cMyBP-C. 12

With respect to pathophysiological phenomena, the reduced phosphorylation of cMyBP-C that has been observed in congestive heart failure 29,59 would contribute to slowed twitch kinetics and reduced twitch force by slowing the rate of cooperative activation of the thin filament. In contrast, the hypercontractility observed in most cases of hypertrophic cardiomyopathy caused by mutations in cMyBP-C suggest an acceleration of the cooperative recruitment of force-generating cross bridges to the thin filament, possibly as a direct consequence of the hypertrophic cardiomyopathy mutation to alter the interaction of cMyBP-C with its binding partner(s) myosin and actin. Further, hypertrophic cardiomyopathy mutations in the MYBPC3 gene resulting in the expression of truncated cMyBP-C often lead to reduced cMyBP-C content, which by itself would be expected to speed the rate of cooperative cross-bridge recruitment, thereby contributing to the cardiac hypercontractility observed in these patients.

Possible Contributions of cMyBP-C Phosphorylation to Relaxation Kinetics in Myocardium

Relaxation of the myocardial twitch is triggered by the reduction of myoplasmic Ca 2+ caused by extrusion of Ca 2+ via the Na + /Ca 2+ exchanger and sequestration of Ca 2+ by the sarcoplasmic reticulum. 60 The initial relaxation of force is delayed with respect to the initial decline in the Ca 2+ transient from its peak (Figure 5). This is most likely caused by ≥2 processes: (1) Ca 2+ continues to bind to troponin when [Ca] 2+ in is declining but still near its peak, and Ca 2+ remains bound to the thin filament even as [Ca] 2+ in declines (2) once a cross bridge binds to the thin filament under the influence of Ca 2+ and neighboring bound cross bridges, the cross bridge completes its cycle of interaction even if [Ca] 2+ in has returned to resting levels, and troponin no longer has Ca 2+ bound to the regulatory site. In support of the first mechanism, force during much of the relaxation phase of the twitch has been observed to follow the force-[Ca] 2+ relationship. 23 With regard to the second mechanism, the relaxation of twitch force is delayed relative to the decay of the intracellular Ca 2+ transient (Figure 5). 12

Figure 5. Time-courses of force and intracellular [Ca] 2+ during the cardiac twitch. Force and intracellular [Ca] 2+ were recorded during twitches (3 Hz stimulus frequency) from mouse myocardium at room temperature. 12 The traces presented here are the averaged traces from multiple muscle preparations and exhibit the time delay between the peak of the Ca 2+ transient and the peak of the twitch.

Based on our proposal that cMyBP-C phosphorylation increases cooperative recruitment of cross bridges, it is difficult to envision how phosphorylation (eg, caused by an adrenergic agonist) would speed twitch relaxation of the twitch because increased cooperativity would be expected to prolong thin filament activation. 52 However, earlier studies of stretch activation responses of skinned myocardium at a fixed [Ca] 2+ showed that the rate of relaxation of force is accelerated by phosphorylation of cMyBP-C (Figure 2). 11 The acceleration is most likely caused by an increased rate of cross-bridge detachment, although the underlying mechanism is not yet known. In the context of a twitch, an increase in detachment rate would be expected to increase the rate of relaxation: the decay of Ca 2+ back to resting levels would slow or eliminate cooperative recruitment of cross bridges, so that relaxation of force would be determined by cross-bridge detachment rate.

Modulation of relaxation rates via cMyBP-C phosphorylation could be important during physiological interventions, such as increased adrenergic tone or increased stimulus frequency. Under these conditions, the decay phase of the Ca 2+ transient is accelerated because of phosphorylation of Ca 2+ handling proteins by the same kinases that phosphorylate cMyBP-C. In these instances, the coordinated phosphorylations of cMyBP-C and Ca 2+ -handling proteins tune the kinetics of cross-bridge detachment to the kinetics of Ca 2+ decay. Without this synchronization of kinetics and particularly the acceleration of cross-bridge detachment, twitch duration would be prolonged, which could depress diastolic filling under conditions of increased stimulation frequency. As an illustration of the importance of synchronization, even though cross-bridge detachment kinetics are accelerated in cMyBP-C null myocardium, cardiac relaxation is slowed in vivo because of a slowing of the Ca 2+ transient. 12

Summary

In the past decade, our understanding of the roles played by cMyBP-C has evolved from an emphasis on structural stabilization of the thick filament to a consensus view that the protein regulates cardiac contractility through phosphorylation-dependent interactions with ≥1 proteins in the cardiac sarcomere. This review has focused on putative interactions with myosin or actin as possible mediators of cMyBP-C regulation of cardiac contraction kinetics, which has narrowed the focus of the review but has not taken into account the observations that cMyBP-C may also bind other sarcomeric proteins, such as myosin regulatory light chain and titin, and may exert regulatory effects that are not controlled by phosphorylation. 61,62 Even with this narrower focus, the range of questions that need to be answered to understand the regulatory roles of cMyBP-C is daunting and important. Does phosphorylation of cMyBP-C directly regulate the kinetics of cross-bridge state transitions or does this involve indirect effects, such as the modulation of the rate of cooperative recruitment of cross-bridges discussed here? Are the mechanisms of phosphorylation-dependent modulation of contractility and relaxation similar or different? Does the phosphorylation state of cMyBP-C influence its binding to myosin, to actin, or to both? What are the contributions of kinases other than PKA to the regulation of cMyBP-C phosphorylation and function? Are the binding phenomena involving myosin and actin that have been observed in simplified biochemical systems functional within the intact filament lattice of myocardium? Which are the key residues in these interactions, and do these residues provide a targeting framework for development of therapeutic interventions designed to modify contractility? How do mutations in cMyBP-C contribute to the altered contractility of inherited or acquired cardiomyopathies?

The complexity implied by this list of questions, which is undoubtedly incomplete, points to the need to use a range of approaches from biochemical and biophysical to intact myocardium and living animals and ultimately human systems, to more fully understand the functions of this intriguing protein. Remarkably, cMyBP-C phosphorylation has only recently emerged as an important player in the regulation of myofibrillar function in heart muscle after several decades of consensus beliefs that such regulation principally involved interactions between and modulation of Ca 2+ delivery systems and myofibrillar Ca 2+ binding proteins within the myocyte. The complexity introduced into this system by regulation via cMyBP-C, and the possibility of other as yet unrecognized regulatory processes, presumably improves the precision and redundancy of control of contraction and relaxation, but also increases the possibility that genetic or environmental derangements might give rise to cardiac disease.


What Is the Role of ATP in Muscle Contraction?

According to Muscle Physiology from the University of California, San Diego, ATP supplies the energy needed by muscles to contract. Ironically, ATP is also needed for muscle relaxation. The chemical stimulates muscle relaxation by disconnecting myosin and actin.

ATP, also known as adenosine triphosphate, is the primary source of energy for many body functions, muscle contraction included, notes Wikipedia. According to Muscle Physiology, muscle contraction and relaxation are achieved through the Lymn-Taylor actomyosin ATPase hydrolysis mechanism. Scientists have yet to fully uncover the link between the Lymn-Taylor actomyosin ATPase hydrolysis mechanism and the mechanical cross-bridge function that also plays a critical role in muscle contraction. However, Lymn and Taylor, the scientists behind the discovery of the Lymn-Taylor actomyosin ATPase hydrolysis mechanism theorize that ATP plays its role through a process that is broken into four parts.

First, ATP binds to myosin, breaking down an actin-myosin bridge and causing muscle contractions to stop. The free myosin and its bridge then move to a point where they can attach to actin. At this point, ATP is broken down into adenosine diphosphate and Pi, generating energy, explains Muscle Physiology. ADP, Pi and the myosin bridge then attach to actin, causing muscle contraction. During the muscle relaxation phase, actin displaces ADP and Pi at the myosin cross bridge. ADP and Pi are then reconstituted into ATP by the body, and the process starts again. Muscle contraction also requires the brain, the nervous system and other body systems to function properly.


Assorted References

Striated muscle contracts to move limbs and maintain posture. Both ends of most striated muscles articulate the skeleton and thus are often called skeletal muscles. They are attached to the bones by tendons, which have some elasticity provided by the proteins collagen and elastin, the major…

…to that seen in skeletal muscle.

Smooth muscle cells contract in response to neuronal or hormonal stimulation, either of which results in an increase in intracellular calcium as calcium enters through membrane channels or is released from intracellular storage sites. The elevated level of calcium in the cell cytoplasm results…

…propose the sliding-filament theory of muscle contraction. An explanation for the conversion of chemical energy to mechanical energy on the molecular level, the theory states that two muscle proteins, actin and myosin, arranged in partially overlapping filaments, slide past each other through the activity of the energy-rich compound adenosine triphosphate…

The contraction of skeletal muscles is an energy-requiring process. In order to perform the mechanical work of contraction, actin and myosin utilize the chemical energy of the molecule adenosine triphosphate (ATP). ATP is synthesized in muscle cells from the storage polysaccharide glycogen, a…

Physiology

Effects of

…the energy for fermentation or muscle contraction depends on a series of reactions now known as glycolysis. In order to show that the conversion of glycogen to lactic acid could provide the necessary energy for muscular contraction, extremely delicate measurements of the heat produced by contracting muscles were required. As…

…of intermittent spasms, or involuntary contractions, of muscles, particularly in the arms and legs and in the larynx, or voice box it results from low levels of calcium in the blood and from alkalosis, an increased alkalinity of the blood and tissues. Tetanus, also called lockjaw, is a state of…

Muscle contraction results from a chain of events that begins with a nerve impulse traveling in the upper motor neuron from the cerebral cortex in the brain to the spinal cord. The nerve impulse then travels in the lower motor neuron from the spinal cord…

Role of

When a signal for muscle contraction is sent along a nerve to a muscle cell, actin and myosin are activated. Myosin works as a motor, hydrolyzing adenosine triphosphate (ATP) to release energy in such a way that a myosin filament moves along an actin filament, causing the two filaments…

…create the force responsible for muscle contraction. When the signal to contract is sent along a nerve to the muscle, the actin and myosin are activated. Myosin works as a motor, hydrolyzing adenosine triphosphate (ATP) to release energy in such a way that a myosin filament moves along an actin…

…brought about by the harmonious contraction and relaxation of selected muscles. Contraction occurs when nerve impulses are transmitted across neuromuscular junctions to the membrane covering each muscle fibre. Most muscles are not continuously contracting but are kept in a state ready to contract. The slightest movement or even the intention…

…role in determining whether muscle contraction occurs.

…level), it is simply called muscle contraction. Muscle contraction occurring as an integrated part of more complex personalistic behaviour may be called reaching this action is an integral part of grasping a pencil, which is part of the more personalistic act of writing to one’s friends.

…to stimulate the muscle to contract rhythmically. That these rhythmic contractions originate in the cardiac muscle can be substantiated by observing cardiac development in the embryo (see above) cardiac pulsations begin before adequate development of nerve fibres. In addition, it can be demonstrated in the laboratory that even fragments of…

The length of the muscle spindle as a whole varies with the contraction phase and the length of the muscle to which it belongs. The length of the sensory midsection, however, may change more or less independently because its motor nerve endings function apart from the innervation of the…

…chain lie the great axial muscles of the body the fibres of this complex group of muscles are more or less parallel to the long axes of the vertebrae. One pair of vertebrae and its associated musculature form the fundamental unit of propulsion. The muscles on the two sides of…


Is the heart more relaxed when stretched or contracted, and how does it affect cross-bridge interactions? - Biology

A translated version of this page (in Estonian) is available at:

  • the impulse arrives at the end bulb,
  • chemical transmitter is released from vesicles (each of which contains 5,000 - 10,000 molecules of acetylcholine) and diffuses across the neuromuscular cleft,
  • the transmitter molecules fill receptor sites in the membrane of the muscle & increase membrane permeability to sodium,
  • sodium then diffuses in & the membrane potential becomes less negative,
  • and, if the threshold potential is reached, an action potential occurs, an impulse travels along the muscle cell membrane, and the muscle contracts.


Some muscles (skeletal muscles) will not contract unless stimulated by neurons other muscles (smooth & cardiac) will contract without nervous stimulation but their contraction can be influenced by the nervous system. Thus, the nervous and muscle systems are closely interconnected. Let's now focus on muscle - what is its structure & how does it work.


Highly magnified view of a neuromuscular junction (Hirsch 2007).

  • excitability - responds to stimuli (e.g., nervous impulses)
  • contractility - able to shorten in length
  • extensibility - stretches when pulled
  • elasticity - tends to return to original shape & length after contraction or extension
  • skeletal:
    • attached to bones & moves skeleton
    • also called striated muscle (because of its appearance under the microscope, as shown in the photo to the left)
    • voluntary muscle
    • smooth (photo on the right)
      • involuntary muscle
      • muscle of the viscera (e.g., in walls of blood vessels, intestine, & other 'hollow' structures and organs in the body)
      • muscle of the heart
      • involuntary


      Skeletal muscle structure

      Skeletal muscles are usually attached to bone by tendons composed of connective tissue. This connective tissue also ensheaths the entire muscle & is called epimysium. Skeletal muscles consist of numerous subunits or bundles called fasicles (or fascicles). Fascicles are also surrounded by connective tissue (called the perimysium) and each fascicle is composed of numerous muscle fibers (or muscle cells). Muscle cells, ensheathed by endomysium, consist of many fibrils (or myofibrils), and these myofibrils are made up of long protein molecules called myofilaments. There are two types of myofilaments in myofibrils: thick myofilaments and thin myofilaments.


      Source: Wikipedia

      Skeletal muscles vary considerably in size, shape, and arrangement of fibers. They range from extremely tiny strands such as the stapedium muscle of the middle ear to large masses such as the muscles of the thigh. Skeletal muscles may be made up of hundreds, or even thousands, of muscle fibers bundled together and wrapped in a connective tissue covering. Each muscle is surrounded by a connective tissue sheath called the epimysium. Fascia, connective tissue outside the epimysium, surrounds and separates the muscles. Portions of the epimysium project inward to divide the muscle into compartments. Each compartment contains a bundle of muscle fibers. Each bundle of muscle fiber is called a fasciculus and is surrounded by a layer of connective tissue called the perimysium. Within the fasciculus, each individual muscle cell, called a muscle fiber, is surrounded by connective tissue called the endomysium. Skeletal muscles have an abundant supply of blood vessels and nerves. Before a skeletal muscle fiber can contract, it has to receive an impulse from a neuron. Generally, an artery and at least one vein accompany each nerve that penetrates the epimysium of a skeletal muscle. Branches of the nerve and blood vessels follow the connective tissue components of the muscle of a nerve cell and with one or more minute blood vessels called capillaries (Source: training.seer.cancer.gov).


      The cell membrane of a muscle cell is called the sarcolemma, and this membrane, like that of neurons, maintains a membrane potential. So, impulses travel along muscle cell membranes just as they do along nerve cell membranes. However, the 'function' of impulses in muscle cells is to bring about contraction. To understand how a muscle contracts, you need to know a bit about the structure of muscle cells.


      Skeletal muscle is the muscle attached to the skeleton. Hundreds or thousands of muscle fibers (cells) bundle together to make up an individual skeletal muscle. Muscle cells are long, cylindrical structures that are bound by a plasma membrane (the sarcolemma) and an overlying basal lamina and when grouped into bundles (fascicles) they make up muscle. The sarcolemma forms a physical barrier against the external environment and also mediates signals between the exterior and the muscle cell.

      The sarcoplasm is the specialized cytoplasm of a muscle cell that contains the usual subcellular elements along with the Golgi apparatus, abundant myofibrils, a modified endoplasmic reticulum known as the sarcoplasmic reticulum (SR), myoglobin and mitochondria. Transverse (T)-tubules invaginate the sarcolemma, allowing impulses to penetrate the cell and activate the SR. As shown in the figure, the SR forms a network around the myofibrils, storing and providing the Ca 2+ that is required for muscle contraction.

      Myofibrils are contractile units that consist of an ordered arrangement of longitudinal myofilaments. Myofilaments can be either thick filaments (comprised of myosin) or thin filaments (comprised primarily of actin). The characteristic 'striations' of skeletal and cardiac muscle are readily observable by light microscopy as alternating light and dark bands on longitudinal sections. The light band, (known as the I-band) is made up of thin filaments, whereas the dark band (known as the A-band) is made up of thick filaments. The Z-line (also known as the Z-disk or Z-band) defines the lateral boundary of each sarcomeric unit. Contraction of the sarcomere occurs when the Z-lines move closer together, making the myofibrils contract, and therefore the whole muscle cell and then the entire muscle contracts (Source: Davies and Nowak 2006).

      The SARCOLEMMA has a unique feature: it has holes in it. These "holes" lead into tubes called TRANSVERSE TUBULES (or T-TUBULES for short). These tubules pass down into the muscle cell and go around the MYOFIBRILS. However, these tubules DO NOT open into the interior of the muscle cell they pass completely through and open somewhere else on the sarcolemma (i.e., these tubules are not used to get things into and out of the muscle cell). The function of T-TUBULES is to conduct impulses from the surface of the cell (SARCOLEMMA) down into the cell and, specifically, to another structure in the cell called the SARCOPLASMIC RETICULUM.


      A muscle fiber is excited via a motor nerve that generates an action potential that spreads along the surface membrane (sarcolemma) and the transverse tubular system into the deeper parts of the muscle fiber. A receptor protein (DHP) senses the membrane depolarization, alters its conformation, and activates the ryanodine receptor (RyR) that releases Ca 2+ from the SR. Ca 2+ then bind to troponin and activates the contraction process (Jurkat-Rott and Lehmann-Horn 2005).


      Sarcoplasmic reticulum (SR) membranes in close proximity to a T-tubule. 'RyR' are proteins the aid in the release of calcium from the SR, 'SERCA2' are proteins that aid in the transport of calcium into the SR (Brette and Orchard 2007).

      The SARCOPLASMIC RETICULUM (SR) is a bit like the endoplasmic reticulum of other cells, e.g., it's hollow. But the primary function of the SARCOPLASMIC RETICULUM is to STORE CALCIUM IONS. Sarcoplasmic reticulum is very abundant in skeletal muscle cells and is closely associated with the MYOFIBRILS (and, therefore, the MYOFILAMENTS). The membrane of the SR is well-equipped to handle calcium: there are "pumps" (active transport) for calcium so that calcium is constantly being "pumped" into the SR from the cytoplasm of the muscle cell (called the SARCOPLASM). As a result, in a relaxed muscle, there is a very high concentration of calcium in the SR and a very low concentration in the sarcoplasm (and, therefore, among the myofibrils & myofilaments). In addition, the membrane has special openings, or "gates", for calcium. In a relaxed muscle, these gates are closed and calcium cannot pass through the membrane. So, the calcium remains in the SR. However, if an impulse travels along the membrane of the SR, the calcium "gates" open &, therefore, calcium diffuses rapidly out of the SR & into the sarcoplasm where the myofibrils & myofilaments are located. This, as you will see, is a key step in muscle contraction.

      Myofibrils are composed of 2 types of myofilaments: thick and thin. In skeletal muscle, these myofilaments are arranged in a very regular, precise pattern: thick myofilaments are typically surrounded by 6 thin myofilaments (end view). In a side view, thin myofilaments can be seen above and below each thick myofilament.


      Myofibril cross-section showing arrangement of thick and thin myofilaments.
      Bar = 100 nm. Image from Widrick et al. (2001)


      Source: Tskhovrebova and Trinick (2003).

      Each myofibril is composed of many subunits lined up end-to-end. These subunits are, of course, composed of myofilaments and are called SARCOMERES. The drawings above & below show just a very small section of the entire length of a myofibril and so you can only see one complete SARCOMERE.

      In each sarcomere, thin myofilaments extend in from each end. Thick myofilaments are found in the middle of the sarcomere and do not extend to the ends. Because of this arrangement, when skeletal muscle is viewed with a microscope, the ends of a sarcomere (where only thin myofilaments are found) appear lighter than the central section (which is dark because of the presence of the thick myofilaments). Thus, a myofibril has alternating light and dark areas because each consists of many sarcomeres lined up end-to-end. This is why skeletal muscle is called STRIATED MUSCLE (i.e., the alternating light and dark areas look like stripes or striations). The light areas are called the I-BANDS and the darker areas the A-BANDS. Near the center of each I-BAND is a thin dark line called the Z-LINE (or Z-membrane in the drawing below). The Z-LINE is where adjacent sarcomeres come together and the thin myofilaments of adjacent sarcomeres overlap slightly. Thus, a sarcomere can be defined as the area between Z-lines.

      Thick myofilaments are composed of a protein called MYOSIN. Each MYOSIN molecule has a tail which forms the core of the thick myofilament plus a head that projects out from the core of the filament. These MYOSIN heads are also commonly referred to as CROSS-BRIDGES.

      The MYOSIN HEAD has several important characteristics:

      • it has ATP-binding sites into which fit molecules of ATP. ATP represents potential energy.
      • it has ACTIN-binding sites into which fit molecules of ACTIN. Actin is part of the thin myofilament and will be discussed in more detail shortly.
      • it has a "hinge"at the point where it leaves the core of the thick myofilament. This allows the head to swivel back and forth, and the "swivelling" is, as will be described shortly, what actually causes muscle contraction.

      The actin molecules (or G-actin as above) are spherical and form long chains. Each thin myofilament contains two such chains that coil around each other. TROPOMYOSIN molecules are lone, thin molecules that wrap around the chain of ACTIN. At the end of each tropomyosin is an TROPONIN molecule. The TROPOMYOSIN and TROPONIN molecules are connected to each other. Each of these 3 proteins plays a key role in muscle contraction:

      • ACTIN - when actin combines with MYOSIN HEAD the ATP associated with the head breaks down into ADP. This reaction released energy that causes the MYOSIN HEAD to SWIVEL.
      • TROPOMYOSIN - In a relaxed muscle, the MYOSIN HEADS of the thick myofilament lie against TROPOMYOSIN molecules of the thin myofilament. As long as the MYOSIN HEADS remain in contact with TROPOMYOSIN nothing happens (i.e., a muscle remains relaxed).
      • TROPONIN - Troponin molecules have binding sites for calcium ions. When a calcium ion fills this site it causes a change in the shape and position of TROPONIN. And, when TROPONIN shifts, it pulls the TROPOMYOSIN to which it is attached. When TROPOMYOSIN is moved, the MYOSIN HEAD that was touching the tropomyosin now comes in contact with an underlying ACTIN molecule.

      1 - Because skeletal muscle is voluntary muscle, contraction requires a nervous impulse. So, step 1 in contraction is when the impulse is transferred from a neuron to the SARCOLEMMA of a muscle cell.

      2 - The impulse travels along the SARCOLEMMA and down the T-TUBULES. From the T-TUBULES, the impulse passes to the SARCOPLASMIC RETICULUM.

      3 - As the impulse travels along the Sarcoplasmic Reticulum (SR), the calcium gates in the membrane of the SR open. As a result, CALCIUM diffuses out of the SR and among the myofilaments.

      4 - Calcium fills the binding sites in the TROPONIN molecules. As noted previously, this alters the shape and position of the TROPONIN which in turn causes movement of the attached TROPOMYOSIN molecule.

      5 - Movement of TROPOMYOSIN permits the MYOSIN HEAD to contact ACTIN (Animations: Myofilament Contraction & Breakdown of ATP and cross-bridge movement).

      6 - Contact with ACTIN causes the MYOSIN HEAD to swivel.

      7 - During the swivel, the MYOSIN HEAD is firmly attached to ACTIN. So, when the HEAD swivels it pulls the ACTIN (and, therefore, the entire thin myofilament) forward. (Obviously, one MYOSIN HEAD cannot pull the entire thin myofilament. Many MYOSIN HEADS are swivelling simultaneously, or nearly so, and their collective efforts are enough to pull the entire thin myofilament).

      8 - At the end of the swivel, ATP fits into the binding site on the cross-bridge & this breaks the bond between the cross-bridge (myosin) and actin. The MYOSIN HEAD then swivels back. As it swivels back, the ATP breaks down to ADP & P and the cross-bridge again binds to an actin molecule.

      9 - As a result, the HEAD is once again bound firmly to ACTIN. However, because the HEAD was not attached to actin when it swivelled back, the HEAD will bind to a different ACTIN molecule (i.e., one further back on the thin myofilament). Once the HEAD is attached to ACTIN, the cross-bridge again swivels, SO STEP 7 IS REPEATED.

      As long as calcium is present (attached to TROPONIN), steps 7 through 9 will continue. And, as they do, the thin myofilament is being "pulled" by the MYOSIN HEADS of the thick myofilament. Thus, the THICK & THIN myofilaments are actually sliding past each other. As this occurs, the distance between the Z-lines of the sarcomere decreases. As sarcomeres get shorter, the myofibril, of course, gets shorter. And, obviously, the muscle fibers (and entire muscle) get shorter.

      Skeletal muscle relaxes when the nervous impulse stops. No impulse means that the membrane of the SARCOPLASMIC RETICULUM is no longer permeable to calcium (i.e., no impulse means that the CALCIUM GATES close). So, calcium no longer diffuses out. The CALCIUM PUMP in the membrane will now transport the calcium back into the SR. As this occurs, calcium ions leave the binding sites on the TOPONIN MOLECULES. Without calcium, TROPONIN returns to its original shape and position as does the attached TROPOMYOSIN. This means that TROPOMYOSIN is now back in position, in contact with the MYOSIN HEAD. So, the MYOSIN head is no longer in contact with ACTIN and, therefore, the muscle stops contracting (i.e., relaxes).

      So, under most circumstances, calcium is the "switch" that turns muscle "on and off" (contracting and relaxing). When a muscle is used for an extended period, ATP supplies can diminish. As ATP concentration in a muscle declines, the MYOSIN HEADS remain bound to actin and can no longer swivel. This decline in ATP levels in a muscle causes MUSCLE FATIGUE. Even though calcium is still present (and a nervous impulse is being transmitted to the muscle), contraction (or at least a strong contraction) is not possible.

      Animations illustrating muscle contraction:

      2 - Myosin head energized via myosin-ATPase activity which converts the bound ATP to ADP + Pi
      3 - Calcium binds to troponin
      4 - Tropomyosin translocates to uncover the cross-bridge binding sites
      5 - The energized myosin binding sites approach the binding sites
      6 - The first myosin head binds to actin
      7 - The bound myosin head releases ADP + Pi, flips and the muscle shortens
      8 - The second myosin head binds to actin
      9 - The first myosin head binds ATP to allow the actin and myosin to unbind
      10 - The second myosin head releases its ADP + Pi, flips & the muscle shortens further
      11 - The second myosin head binds to ATP to allow the actin and myosin to unbind
      12 - The second myosin head unbinds from the actin, flips back and is ready for the next cycle
      13 - The cross-bridge cycle is terminated by the loss of calcium from the troponin
      14 - Tropomyosin translocates to cover the cross-bridge binding sites
      15 - The calcium returns to the sarcoplasmic reticulum, the muscle relaxes & returns to the resting state

      Types of contractions:

      Twitch - the response of a skeletal muscle to a single stimulation (or action potential):

      • latent period - no change in length time during which impulse is traveling along sarcolemma & down t-tubules to sarcoplasmic reticulum, calcium is being released, and so on (in other words, muscle cannot contract instantaneously!)
      • contraction period - tension increases (cross-bridges are swivelling)
      • relaxation period - muscle relaxes (tension decreases) & tends to return to its original length

      An important characteristic of skeletal muscle is its ability to contract to varying degrees. A muscle, like the biceps, contracts with varying degrees of force depending on the circumstance (this is also referred to as a graded response). Muscles do this by a process called summation, specifically by motor unit summation and wave summation.

      Motor Unit Summation - the degree of contraction of a skeletal muscle is influenced by the number of motor units being stimulated (with a motor unit being a motor neuron plus all of the muscle fibers it innervates see diagram below). Skeletal muscles consist of numerous motor units and, therefore, stimulating more motor units creates a stronger contraction.

      Wave Summation - an increase in the frequency with which a muscle is stimulated increases the strength of contraction. This is illustrated in (b). With rapid stimulation (so rapid that a muscle does not completely relax between successive stimulations), a muscle fiber is re-stimulated while there is still some contractile activity. As a result, there is a 'summation' of the contractile force. In addition, with rapid stimulation there isn't enough time between successive stimulations to remove all the calcium from the sarcoplasm. So, with several stimulations in rapid succession, calcium levels in the sarcoplasm increase. More calcium means more active cross-bridges and, therefore, a stronger contraction. (Wiley animation)

      If a muscle fiber is stimulated so rapidly that it does not relax at all between stimuli, a smooth, sustained contraction called tetanus occurs (illustrated by the straight line in c above & in the diagram below).

      • involuntary muscle innervated by the Autonomic Nervous System (visceral efferent fibers)
      • found primarily in the walls of hollow organs & tubes
      • spindle-shaped cells typically arranged in sheets
      • cells do not have t-tubules & have very little sarcoplasmic reticulum
      • cells do not contain sarcomeres (so are not striated) but are made up of thick & thin myofilaments. Thin filaments in smooth muscle do not contain troponin.
      • calcium does not bind to troponin but, rather, to a protein called calmodulin. The calcium-calmodulin complex 'activates' myosin which then binds to actin & contraction (swivelling of cross-bridges) begins.


      Two types of smooth muscle:

        • found in the walls of hollow organs (e.g., small blood vessels, digestive tract, urinary system, & reproductive system)
        • multiple fibers contract as a unit (because impulses travel easily across gap junctions from cell to cell) &, in some cases, are self-excitable (generate spontaneous action potentials & contractions)
          2 - multiunit smooth muscle
          • consists of motor units that are activated by nervous stimulation
          • found in the walls of large blood vessels, in the eye (adusting the shape of the lens to permit accommodation & the size of the pupil to adjust the amount of light entering the eye), & at the base of hair follicle (the 'goose bump' muscles)

          Brette, F., and C. Orchard. 2007. Resurgence of cardiac T-tubule research. Physiology 22: 167-173.

          Davies, K. E., and K. J. Nowak. 2006. Molecular mechanisms of muscular dystrophies: old and new players. Nature Reviews Molecular Cell Biology 7: 762-773.

          Hirsch, N. P. 2007. Neuromuscular junction in health and disease. British Journal of Anaesthesia 99: 132-138.

          Jurkat-Rott, K., and F. Lehmann-Horn. 2005. Muscle channelopathies and critical points in functional and genomic studies. Journal of Clinical Investigation 115: 2000-2009.

          Tskhovrebova, L., and J. Trinick. 2003. Titin: properties and family relationships. Nature Reviews Molecular Cell Biology 4: 679-689.

          Widrick, J. J., J. G. Romatowski , K. M. Norenberg , S. T. Knuth , J. L. W. Bain , D. A. Riley , S. W. Trappe , T. A. Trappe , D. L. Costill , and R. H. Fitts. 2001. Functional properties of slow and fast gastrocnemius muscle fibers after a 17-day spaceflight. Journal of Applied Physiology 90: 2203-2211.


          Nervous System Control of Muscle Tension

          To move an object, referred to as load, the sarcomeres in the muscle fibers of the skeletal muscle must shorten. The force generated by the contraction of the muscle (or shortening of the sarcomeres) is called muscle tension . However, muscle tension also is generated when the muscle is contracting against a load that does not move, resulting in two main types of skeletal muscle contractions: isotonic contractions and isometric contractions.

          In isotonic contractions , where the tension in the muscle stays constant, a load is moved as the length of the muscle changes (shortens). There are two types of isotonic contractions: concentric and eccentric. A concentric contraction involves the muscle shortening to move a load. An example of this is the biceps brachii muscle contracting when a hand weight is brought upward with increasing muscle tension. As the biceps brachii contract, the angle of the elbow joint decreases as the forearm is brought toward the body. Here, the biceps brachii contracts as sarcomeres in its muscle fibers are shortening and cross-bridges form the myosin heads pull the actin. An eccentric contraction occurs as the muscle tension diminishes and the muscle lengthens. In this case, the hand weight is lowered in a slow and controlled manner as the amount of cross-bridges being activated by nervous system stimulation decreases. In this case, as tension is released from the biceps brachii, the angle of the elbow joint increases. Eccentric contractions are also used for movement and balance of the body.

          An isometric contraction occurs as the muscle produces tension without changing the angle of a skeletal joint. Isometric contractions involve sarcomere shortening and increasing muscle tension, but do not move a load, as the force produced cannot overcome the resistance provided by the load. For example, if one attempts to lift a hand weight that is too heavy, there will be sarcomere activation and shortening to a point, and ever-increasing muscle tension, but no change in the angle of the elbow joint. In everyday living, isometric contractions are active in maintaining posture and maintaining bone and joint stability. However, holding your head in an upright position occurs not because the muscles cannot move the head, but because the goal is to remain stationary and not produce movement. Most actions of the body are the result of a combination of isotonic and isometric contractions working together to produce a wide range of outcomes ((Figure)).

          All of these muscle activities are under the exquisite control of the nervous system. Neural control regulates concentric, eccentric and isometric contractions, muscle fiber recruitment, and muscle tone. A crucial aspect of nervous system control of skeletal muscles is the role of motor units.

          Motor Units

          As you have learned, every skeletal muscle fiber must be innervated by the axon terminal of a motor neuron in order to contract. Each muscle fiber is innervated by only one motor neuron. The actual group of muscle fibers in a muscle innervated by a single motor neuron is called a motor unit . The size of a motor unit is variable depending on the nature of the muscle.

          A small motor unit is an arrangement where a single motor neuron supplies a small number of muscle fibers in a muscle. Small motor units permit very fine motor control of the muscle. The best example in humans is the small motor units of the extraocular eye muscles that move the eyeballs. There are thousands of muscle fibers in each muscle, but every six or so fibers are supplied by a single motor neuron, as the axons branch to form synaptic connections at their individual NMJs. This allows for exquisite control of eye movements so that both eyes can quickly focus on the same object. Small motor units are also involved in the many fine movements of the fingers and thumb of the hand for grasping, texting, etc.

          A large motor unit is an arrangement where a single motor neuron supplies a large number of muscle fibers in a muscle. Large motor units are concerned with simple, or “gross,” movements, such as powerfully extending the knee joint. The best example is the large motor units of the thigh muscles or back muscles, where a single motor neuron will supply thousands of muscle fibers in a muscle, as its axon splits into thousands of branches.

          There is a wide range of motor units within many skeletal muscles, which gives the nervous system a wide range of control over the muscle. The small motor units in the muscle will have smaller, lower-threshold motor neurons that are more excitable, firing first to their skeletal muscle fibers, which also tend to be the smallest. Activation of these smaller motor units, results in a relatively small degree of contractile strength (tension) generated in the muscle. As more strength is needed, larger motor units, with bigger, higher-threshold motor neurons are enlisted to activate larger muscle fibers. This increasing activation of motor units produces an increase in muscle contraction known as recruitment . As more motor units are recruited, the muscle contraction grows progressively stronger. In some muscles, the largest motor units may generate a contractile force of 50 times more than the smallest motor units in the muscle. This allows a feather to be picked up using the biceps brachii arm muscle with minimal force, and a heavy weight to be lifted by the same muscle by recruiting the largest motor units.

          When necessary, the maximal number of motor units in a muscle can be recruited simultaneously, producing the maximum force of contraction for that muscle, but this cannot last for very long because of the energy requirements to sustain the contraction. To prevent complete muscle fatigue, motor units are generally not all simultaneously active, but instead some motor units rest while others are active, which allows for longer muscle contractions. The nervous system uses recruitment as a mechanism to efficiently utilize a skeletal muscle.

          The Length-Tension Range of a Sarcomere

          When a skeletal muscle fiber contracts, myosin heads attach to actin to form cross-bridges followed by the thin filaments sliding over the thick filaments as the heads pull the actin, and this results in sarcomere shortening, creating the tension of the muscle contraction. The cross-bridges can only form where thin and thick filaments already overlap, so that the length of the sarcomere has a direct influence on the force generated when the sarcomere shortens. This is called the length-tension relationship.

          The ideal length of a sarcomere to produce maximal tension occurs at 80 percent to 120 percent of its resting length, with 100 percent being the state where the medial edges of the thin filaments are just at the most-medial myosin heads of the thick filaments ((Figure)). This length maximizes the overlap of actin-binding sites and myosin heads. If a sarcomere is stretched past this ideal length (beyond 120 percent), thick and thin filaments do not overlap sufficiently, which results in less tension produced. If a sarcomere is shortened beyond 80 percent, the zone of overlap is reduced with the thin filaments jutting beyond the last of the myosin heads and shrinks the H zone, which is normally composed of myosin tails. Eventually, there is nowhere else for the thin filaments to go and the amount of tension is diminished. If the muscle is stretched to the point where thick and thin filaments do not overlap at all, no cross-bridges can be formed, and no tension is produced in that sarcomere. This amount of stretching does not usually occur, as accessory proteins and connective tissue oppose extreme stretching.

          The Frequency of Motor Neuron Stimulation

          A single action potential from a motor neuron will produce a single contraction in the muscle fibers of its motor unit. This isolated contraction is called a twitch . A twitch can last for a few milliseconds or 100 milliseconds, depending on the muscle type. The tension produced by a single twitch can be measured by a myogram , an instrument that measures the amount of tension produced over time ((Figure)). Each twitch undergoes three phases. The first phase is the latent period , during which the action potential is being propagated along the sarcolemma and Ca ++ ions are released from the SR. This is the phase during which excitation and contraction are being coupled but contraction has yet to occur. The contraction phase occurs next. The Ca ++ ions in the sarcoplasm have bound to troponin, tropomyosin has shifted away from actin-binding sites, cross-bridges formed, and sarcomeres are actively shortening to the point of peak tension. The last phase is the relaxation phase , when tension decreases as contraction stops. Ca ++ ions are pumped out of the sarcoplasm into the SR, and cross-bridge cycling stops, returning the muscle fibers to their resting state.

          Although a person can experience a muscle “twitch,” a single twitch does not produce any significant muscle activity in a living body. A series of action potentials to the muscle fibers is necessary to produce a muscle contraction that can produce work. Normal muscle contraction is more sustained, and it can be modified by input from the nervous system to produce varying amounts of force this is called a graded muscle response . The frequency of action potentials (nerve impulses) from a motor neuron and the number of motor neurons transmitting action potentials both affect the tension produced in skeletal muscle.

          The rate at which a motor neuron fires action potentials affects the tension produced in the skeletal muscle. If the fibers are stimulated while a previous twitch is still occurring, the second twitch will be stronger. This response is called wave summation , because the excitation-contraction coupling effects of successive motor neuron signaling is summed, or added together ((Figure)a). At the molecular level, summation occurs because the second stimulus triggers the release of more Ca ++ ions, which become available to activate additional sarcomeres while the muscle is still contracting from the first stimulus. Summation results in greater contraction of the motor unit.

          If the frequency of motor neuron signaling increases, summation and subsequent muscle tension in the motor unit continues to rise until it reaches a peak point. The tension at this point is about three to four times greater than the tension of a single twitch, a state referred to as incomplete tetanus. During incomplete tetanus, the muscle goes through quick cycles of contraction with a short relaxation phase for each. If the stimulus frequency is so high that the relaxation phase disappears completely, contractions become continuous in a process called complete tetanus ((Figure)b).

          During tetanus, the concentration of Ca ++ ions in the sarcoplasm allows virtually all of the sarcomeres to form cross-bridges and shorten, so that a contraction can continue uninterrupted (until the muscle fatigues and can no longer produce tension).

          Treppe

          When a skeletal muscle has been dormant for an extended period and then activated to contract, with all other things being equal, the initial contractions generate about one-half the force of later contractions. The muscle tension increases in a graded manner that to some looks like a set of stairs. This tension increase is called treppe , a condition where muscle contractions become more efficient. It’s also known as the “staircase effect” ((Figure)).

          It is believed that treppe results from a higher concentration of Ca ++ in the sarcoplasm resulting from the steady stream of signals from the motor neuron. It can only be maintained with adequate ATP.

          Muscle Tone

          Skeletal muscles are rarely completely relaxed, or flaccid. Even if a muscle is not producing movement, it is contracted a small amount to maintain its contractile proteins and produce muscle tone . The tension produced by muscle tone allows muscles to continually stabilize joints and maintain posture.

          Muscle tone is accomplished by a complex interaction between the nervous system and skeletal muscles that results in the activation of a few motor units at a time, most likely in a cyclical manner. In this manner, muscles never fatigue completely, as some motor units can recover while others are active.

          The absence of the low-level contractions that lead to muscle tone is referred to as hypotonia , and can result from damage to parts of the central nervous system (CNS), such as the cerebellum, or from loss of innervations to a skeletal muscle, as in poliomyelitis. Hypotonic muscles have a flaccid appearance and display functional impairments, such as weak reflexes. Conversely, excessive muscle tone is referred to as hypertonia , accompanied by hyperreflexia (excessive reflex responses), often the result of damage to upper motor neurons in the CNS. Hypertonia can present with muscle rigidity (as seen in Parkinson’s disease) or spasticity, a phasic change in muscle tone, where a limb will “snap” back from passive stretching (as seen in some strokes).

          Chapter Review

          The number of cross-bridges formed between actin and myosin determines the amount of tension produced by a muscle. The length of a sarcomere is optimal when the zone of overlap between thin and thick filaments is greatest. Muscles that are stretched or compressed too greatly do not produce maximal amounts of power. A motor unit is formed by a motor neuron and all of the muscle fibers that are innervated by that same motor neuron. A single contraction is called a twitch. A muscle twitch has a latent period, a contraction phase, and a relaxation phase. A graded muscle response allows variation in muscle tension. Summation occurs as successive stimuli are added together to produce a stronger muscle contraction. Tetanus is the fusion of contractions to produce a continuous contraction. Increasing the number of motor neurons involved increases the amount of motor units activated in a muscle, which is called recruitment. Muscle tone is the constant low-level contractions that allow for posture and stability.

          Review Questions

          During which phase of a twitch in a muscle fiber is tension the greatest?


          REVIEW article

          Walter E. Knight 1 , Hadi R. Ali 1 , Stephanie J. Nakano 2 , Cortney E. Wilson 1 , Lori A. Walker 1*† and Kathleen C. Woulfe 1*†
          • 1 Department of Medicine, Division of Cardiology, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
          • 2 Department of Pediatrics, Division of Cardiology, Children’s Hospital, University of Colorado Anschutz Medical Campus, Aurora, CO, United States

          Cardiovascular disease continues to be the leading cause of morbidity and mortality in the United States and thousands of manuscripts each year are aimed at elucidating mechanisms underlying cardiac disease. The methods for quantifying cardiac performance are quite varied, with each technique assessing unique features of cardiac muscle mechanical properties. Accordingly, in this review, we discuss current ex vivo methods for quantifying cardiac muscle performance, highlighting what can be learned from each method, and how each technique can be used in conjunction to complement others for a more comprehensive understanding of cardiac function. Importantly, cardiac function can be assessed at several different levels, from the whole organ down to individual protein-protein interactions. Here, we take a reductionist view of methods that are commonly used to measure the distinct aspects of cardiac mechanical function, beginning with whole heart preparations and finishing with the in vitro motility assay. While each of the techniques are individually well-documented in the literature, there is a significant need for a comparison of the techniques, delineating the mechanical parameters that can are best measured with each technique, as well as the strengths and weaknesses inherent to each method. Additionally, we will consider complementary techniques and how these methods can be used in combination to improve our understanding of cardiac mechanical function. By presenting each of these methods, with their strengths and limitations, in a single manuscript, this review will assist cardiovascular biologists in understanding the existing literature on cardiac mechanical function, as well as designing future experiments.


          Contraction of the isolated muscle strip

          The mechanics of cardiac myocyte contraction can be studied in the laboratory by examining the behaviour of an isolated muscle strip (Fig. 4). The papillary muscle is convenient for this as its fibres run in roughly the same direction. The muscle is placed under an initial tension or preload. If the muscle strip is anchored at both ends and stimulated it undergoes isometric contraction. The tension generated during isometric contraction increases with increasing initial length (Fig. 4 a ). Alteration in initial fibre length is analogous to preload. Increasing venous return to the heart results in an increased left ventricular end diastolic volume, thereby increasing fibre length. This produces an increase in the force of contraction and an increased stroke volume resulting in the familiar Starling curve. The conventional explanation for this is that at normal resting length, the overlap of actin and myosin is not optimal. Increasing the initial length improves the degree of overlap and therefore increases the tension developed. It has become clear in recent years that this mechanism is unlikely to account for the shape of the Starling curve under physiological conditions. Several other possible mechanisms have been implicated. Lengthening the muscle increases the sensitivity of troponin to calcium (length-dependent calcium sensitivity) and can also lead to enhanced intracellular free calcium.

          Contractile properties of myocardial muscle. Left: Simplified arrangement to study contraction of isolated cat papillary muscle. In isotonic contractions the weight labelled ‘afterload’ is picked up as soon as shortening begins. The weight labelled preload sets the resting length. If the preload is clamped in place contraction becomes isometric. Right: Three fundamental relations: ( a ) isometric contraction at increasing lengths, ( b and c ) isotonic contractions beginning from two different resting lengths (8 and 10 mm). Contractile force, velocity, and shortening are all increased by stretching the relaxed muscle. 3

          Contractile properties of myocardial muscle. Left: Simplified arrangement to study contraction of isolated cat papillary muscle. In isotonic contractions the weight labelled ‘afterload’ is picked up as soon as shortening begins. The weight labelled preload sets the resting length. If the preload is clamped in place contraction becomes isometric. Right: Three fundamental relations: ( a ) isometric contraction at increasing lengths, ( b and c ) isotonic contractions beginning from two different resting lengths (8 and 10 mm). Contractile force, velocity, and shortening are all increased by stretching the relaxed muscle. 3

          If the muscle is able to shorten, but has to lift a weight, this is known as isotonic contraction. The weight moved by the muscle strip represents afterload. As afterload increases, both the amount and velocity of shortening decreases (Fig. 4 b and c ). Conversely, reducing the afterload enhances shortening, a fact of considerable importance in the management of the failing heart. If the preload is increased by stretching the muscle and the experiment repeated, both velocity and shortening are enhanced. (Fig. 4 b and c ).

          In vivo, the initial phase of cardiac contraction, from the closure of the mitral and tricuspid valves to the opening of the aortic and pulmonary valves, is isotonic. Tension is developed, but the ventricle does not eject blood, as there is no muscle fibre shortening. After the opening of the aortic and pulmonary valves, contraction becomes isotonic, tension is maintained, but blood is ejected and tonic shortening occurs.


          Watch the video: Γέφυρα Ρίου Αντίρριου-National Geographic Rio Antirio Bridge (July 2022).


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