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Calcium, Cross-Bridges, and the Frank-Starling Relationship

Franklin Fuchs and Stephen H. Smith

F. Fuchs is in the Department of Cell Biology and Physiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261. S. H. Smith is in the Department of Physiology and Biophysics, University of Illinois College of Medicine, Chicago, IL 60612.

	Abstract

 
The steep relationship between active force and length in cardiac muscle is based on a length dependence of myofilament Ca²⁺ sensitivity. However, it is not muscle length but the lateral spacing between actin and myosin filaments that sets the level of Ca²⁺ sensitivity, mainly through modulation of myosin-mediated activation of the thin filament.

	Introduction

Top Introduction The response of cardiac... Length-dependent Ca2+... Thin filament activation Strong-binding cross-bridges and... Length vs. width Length-dependent activation and... Problems for future... Summary References

 
At the turn of the 20th century, Otto Frank and Ernest Starling carried out their classic studies on the relationship between end diastolic volume and systolic function in the isolated heart. Their findings, still valid, have since been absorbed by many generations of students of medicine and physiology, and they invariably enter into the discussion of such subjects as cardiac output regulation, exercise, and congestive heart failure. Yet at the beginning of the 21st century, investigators are still trying to identify the intracellular signaling pathways responsible for the seemingly simple relationship between myocardial fiber length and the work output of the heart. Recent years have seen a proliferation of studies of length-dependent behavior of intact cardiac muscle, isolated cardiac myocytes, and various types of skinned fiber preparations in which the membranes have been removed, usually by detergent treatment. These studies together have provided a reasonably convincing picture of how relatively small changes in sarcomere length can be transduced into large changes in developed force. However, the detailed molecular interactions that adjust molecular motor function to myocyte length remain to be clarified. Further progress can be expected with the current availability of powerful molecular-genetic techniques, which can probe the relationship between specific molecular alterations and functional changes at the cell and organ levels.

	The response of cardiac muscle to stretch

Top Introduction The response of cardiac... Length-dependent Ca2+... Thin filament activation Strong-binding cross-bridges and... Length vs. width Length-dependent activation and... Problems for future... Summary References

 
If a strip of cardiac muscle is mounted in a muscle chamber under isometric conditions and stimulated at a fixed frequency, an increase in sarcomere length along the ascending limb of the force-length curve (sarcomere length 1.7–2.4 µm) produces a biphasic increase in twitch force. Immediately following the initial stretch, there is a large increase in force that is unaccompanied by a significant change in the amount of Ca²⁺ released into the cytoplasm (1). After a delay of several minutes, there is a further slow increase in force that occurs in conjunction with a slow increase in the height of the Ca²⁺ transient. The published data show considerable variability, but in most studies the slow phase accounts for ~20–30% of the total force increase in response to the stretch. The initial force increase is primarily due to an increase in myofilament Ca²⁺ sensitivity, with possibly a small contribution due simply to the change in filament overlap (1). The secondary slow force increase involves changes in intracellular Ca²⁺ homeostasis that occur in response to cell deformation. It is very likely that the slow response is the expression at the cellular level of the gradual increase in ventricular contractility that is seen in the intact, beating heart following the imposition of an increased afterload (homeometric autoregulation). Thus phase 1 is a myofilament-mediated response, whereas phase 2 is most likely a membrane-mediated response. The Frank-Starling phenomenon has been equated by most authors with the initial response to stretch, and it is this phase that will be the focus of this review.

	Length-dependent Ca2+ sensitivity

Top Introduction The response of cardiac... Length-dependent Ca2+... Thin filament activation Strong-binding cross-bridges and... Length vs. width Length-dependent activation and... Problems for future... Summary References

 
Early studies with intact cardiac muscles (see Ref. 1 for review) provided strong evidence that the activation process is length dependent. Especially relevant were studies showing that the steep ascending limb of the cardiac force-length curve was shifted upward and reduced in slope by positive inotropic interventions that promoted increased Ca²⁺ entry (increased heart rate, increased extracellular Ca²⁺). Thus the shape of the cardiac force-length curve was not simply a function of filament lattice geometry, as appeared to be the case for tetanically stimulated skeletal muscle (Fig. 1). Two papers published in 1982 marked the beginning of the modern phase of research into the subcellular origin of the Frank-Starling relationship. Allen and Kurihara (2) microinjected the Ca²⁺-sensitive photoprotein aequorin into myocytes of papillary muscles and trabeculae from rat and cat ventricles and made the first systematic observations of both active force and Ca²⁺ transients as a function of muscle length. As indicated above, they showed that immediately following an increase in muscle length there was a large increase in force with no significant change in the height of the Ca²⁺ transient, a response that they interpreted as indicating an increase in myofilament Ca²⁺ sensitivity. With stimulation extended over a period of several minutes, there were parallel increases in both force and the height of the Ca²⁺ transient. Concurrently, Hibberd and Jewell (9) used detergent-skinned rat trabeculae immersed in Ca²⁺-buffered solutions to study the effect of sarcomere length on the relationship between force and pCa. They showed that with an increase in sarcomere length from 1.9 to 2.4 µm there was a clear leftward shift of the force-pCa curve, denoting an increase in Ca²⁺ sensitivity. The latter is generally quantified in terms of the pCa associated with half-maximal force generation (pCa₅₀). These fundamental observations have been repeatedly confirmed, and it is now accepted that a length-dependent shift in Ca²⁺ sensitivity is the key component of the Frank-Starling relation. Associated with the altered Ca²⁺ sensitivity is a parallel change in the affinity between Ca²⁺ and the regulatory binding site on cardiac troponin C. These findings raise a fundamental question: how does the regulatory protein complex that mediates Ca²⁺ activation "sense" muscle length? As will be discussed below, this question is closely connected to the more basic problem of how the contractile system is activated by the sudden rise in cytosolic Ca²⁺ triggered by the action potential.

View larger version (18K): [in this window] [in a new window]   FIGURE 1. Schematic illustration of the length dependence of normalized isometric tetanic force in skeletal muscle and normalized isometric twitch force in cardiac muscle. Length has been normalized with respect to that length at which force is maximal for each type of muscle. Note that in the physiological length range (80–100% Lmax) the cardiac force-length curve is much steeper than the skeletal force-length curve, despite the fact that actin and myosin filament lengths are similar. See Ref. 1 for a discussion of filament geometry in striated muscle. Also illustrated is the way in which the position of the cardiac force-length curve varies with inotropic state.

	Thin filament activation

Top Introduction The response of cardiac... Length-dependent Ca2+... Thin filament activation Strong-binding cross-bridges and... Length vs. width Length-dependent activation and... Problems for future... Summary References

With the introduction of the "steric blocking" model in the 1970s, a key function in Ca²⁺ activation was assigned to Tm (7). Since each Tm overlaps seven actin subunits and has attached to it one Tn, the complex A₇TmTn was considered to be the fundamental thin filament regulatory unit. This unit could exist in an "on" or "off" state depending on the position of the Tm in the groove of the actin filament. Early X-ray diffraction studies indicated that the binding of Ca²⁺ to TnC caused the Tm to shift from the periphery toward the center of the groove, thereby allowing myosin heads easier access to binding sites on actin. In this simple two-state model, the Ca²⁺ ion is the sole activator of the thin filament. However, it has been known for some time that there is a second thin filament activator, and that is myosin itself. Myosin activation is most simply demonstrated by placing a skinned muscle fiber in a Ca²⁺-free relaxing solution and gradually lowering the MgATP concentration. Actin and myosin bind tightly at very low MgATP concentrations. When MgATP concentration is sufficiently low (~10^–5 M), the attachment of a critical number of strong-binding cross-bridges (rigor bridges) to actin causes a cooperative upregulation of the thin filament, seen as an increase in myosin ATPase activity and the development of tension. In addition, the attachment of rigor bridges to actin causes an increase in Ca²⁺-TnC binding affinity. There is now ample evidence that the force-generating cross-bridges formed under more physiological conditions (3-5 mM MgATP, 10^–7–10^–5 M Ca²⁺) cause the same cooperative activation of the thin filament. A complete review of this evidence is beyond the scope of this article, but we may cite biochemical experiments with reconstituted thin filaments that showed that if the ratio of myosin heads to actin subunits was sufficiently low the myosin ATPase activity remained low even in the presence of Ca²⁺ concentrations that would fully saturate the binding sites on TnC (7, 11). At the structural level, electron microscopic and X-ray diffraction studies have shown that the amount of Tm movement produced by Ca²⁺ binding to TnC in isolated thin filaments (in the absence of myosin) was significantly less than that seen when myosin heads were strongly bound to actin (15). Thus full activation of the thin filament results from a concerted effect of Ca²⁺ binding to TnC and myosin binding to actin.

Biochemical studies carried out during the past decade by Geeves, Lehrer, and co-workers (11) have provided strong support for a three-state model of thin filament activation. According to this model, in the presence of physiological concentrations of MgATP, but in the absence of Ca²⁺, Tm is in its optimal blocking position and the cross-bridges are largely detached from actin ("blocked" state). With the binding of Ca²⁺ to TnC, there is a partial movement of Tm, which allows the myosin heads to bind weakly to actin ("closed" state). With Ca²⁺ still bound to the regulatory site on TnC, the weak actin-myosin complex (A state) can then isomerize to a strong-binding complex (R state), which is responsible for the generation of force and which shifts the thin filament into the "open" state. The A R transition forces Tm further into the groove of the actin filament, thereby allowing for the recruitment of more cross-bridges. This recruitment makes a major contribution to the highly cooperative nature of the force-pCa relationship. As shown by Lehrer and Geeves (11), this system has the main features of an allosteric regulatory system in which myosin (or myosin-ADP complex) is the true activating ligand, actin is the catalytic subunit, Tm is the regulatory subunit, and the Tn ± Ca²⁺ is the allosteric effector (positive when Ca²⁺ is bound to TnC, negative when Ca²⁺ is dissociated from TnC).

	Strong-binding cross-bridges and Ca2+ sensitivity

Top Introduction The response of cardiac... Length-dependent Ca2+... Thin filament activation Strong-binding cross-bridges and... Length vs. width Length-dependent activation and... Problems for future... Summary References

 
Returning to the question first posed, evidence has been accumulating that sarcomere length modulates the level of Ca²⁺ sensitivity through variation in the number of strong-binding actin-myosin interactions. The basic idea is that with increase in sarcomere length along the ascending limb of the force-length curve there is a more favorable disposition of the myosin heads relative to actin, thereby increasing the probability of strong-binding actin-myosin interactions taking place. That is, an increase in sarcomere length favors myosin-mediated activation of the thin filament. In support of this view, measurements of radioactive Ca²⁺ binding to cTnC in skinned bovine cardiac fibers showed that the length dependence of the Ca²⁺-cTnC interaction was based on a length dependence of strong-binding actin-myosin interactions rather than length itself (10). The length dependence of Ca²⁺ binding was eliminated by cross-bridge interaction inhibitors that prevented either rigor or force-generating bridges from attaching to actin. More recently, Fitzsimons and Moss (5) showed that labeling of the actin of skinned cardiac myocytes with strong-binding myosin heads (chemically modified) reversibly eliminated the length dependence of Ca²⁺ sensitivity. Thus changes in the geometry of the myofilament lattice modify Ca²⁺ sensitivity via effects on myosin-mediated activation of the thin filament.

	Length vs. width

Top Introduction The response of cardiac... Length-dependent Ca2+... Thin filament activation Strong-binding cross-bridges and... Length vs. width Length-dependent activation and... Problems for future... Summary References

 
The hypothesis that strong-binding cross-bridge interactions are responsible for the length modulation of Ca²⁺ sensitivity encountered an early difficulty with the observation, first made in the 1970s, that in both skeletal and cardiac muscles the Ca²⁺ sensitivity is increased when skinned fibers are stretched along the descending limb of the force-length curve (1). In this region, the potential for cross-bridge interactions should decrease as the overlap of actin and myosin filaments is diminished. An alternative hypothesis that takes this objection into account is that the Ca²⁺ sensitivity is determined not by sarcomere length but by a derivative of sarcomere length, namely interfilament spacing. The filament lattice of striated muscle is an isovolumic system. Hence, as the sarcomere length is increased, the lateral spacing between actin and myosin filaments is reduced. If this spacing influences the probability of cross-bridge attachment, the Ca²⁺ sensitivity would not be a simple function of actin-myosin overlap but would also depend on interfilament spacing.

Interfilament spacing at a fixed sarcomere length can be changed quite easily by immersing skinned fiber preparations in buffer solutions containing a high-molecular-weight polymer that cannot diffuse into the interfilament space. The resulting osmotic withdrawal of fluid from the interfilament space causes a reversible reduction in fiber diameter, the magnitude of which is a function of the polymer concentration. One of the more commonly used polymers is Dextran T-500. Early studies with skinned skeletal muscle fibers showed that moderate lattice compression at a constant sarcomere length caused an increase in Ca²⁺ sensitivity (1). More quantitative studies with skinned cardiac myocytes have shown that if a given reduction in fiber diameter is produced by either stretch or osmotic compression the observed changes in Ca²⁺ sensitivity are in quite close agreement (12). In a study in our laboratory (6), skinned muscle bundles at different sarcomere lengths were subjected to varying degrees of osmotic compression with Dextran T-500. It was then possible to analyze both Ca²⁺ sensitivity and Ca²⁺-cTnC affinity as a function of sarcomere length under conditions in which interfilament spacing could change with sarcomere length or remain relatively constant. It was clear that both Ca²⁺ sensitivity and Ca²⁺ binding were correlated with interfilament spacing and not at all with sarcomere length (Fig. 2). Thus the shift in Ca²⁺ sensitivity that underlies the Frank-Starling relation depends not on a change in sarcomere length per se but on the change in lateral separation between actin and myosin filaments.

View larger version (15K): [in this window] [in a new window]   FIGURE 2. The relationship between the Ca2+ concentration half-maximal force generation (pCa50) and sarcomere length in skinned bovine ventricular muscle under conditions in which the interfilament spacing was free to change (•) with increase in sarcomere length (no Dextran T-500 added) and in which the muscle diameter was maintained at a constant value () by appropriate addition of Dextran T-500 at each sarcomere length [redrawn from Fuchs and Wang (6)].

	Length-dependent activation and the three-state model

Top Introduction The response of cardiac... Length-dependent Ca2+... Thin filament activation Strong-binding cross-bridges and... Length vs. width Length-dependent activation and... Problems for future... Summary References

View larger version (22K): [in this window] [in a new window]   FIGURE 3. The relationship between normalized force and pCa at long and short sarcomere lengths (S.L.). The data were obtained with skinned cardiac muscle bundles at different KCl concentrations as indicated [redrawn from Smith and Fuchs (13)].

View larger version (17K): [in this window] [in a new window]   FIGURE 4. Simplified scheme based on the Geeves-Lehrer 3-state model (7, 11) showing how interfilament spacing might influence thin filament activation. Reduction in interfilament spacing promotes an increase in the population of weakly bound cross-bridges (A state). Tm, tropomyosin.

	Problems for future investigation

Top Introduction The response of cardiac... Length-dependent Ca2+... Thin filament activation Strong-binding cross-bridges and... Length vs. width Length-dependent activation and... Problems for future... Summary References

Although it appears that the length-dependent shift in Ca²⁺ sensitivity can be almost fully accounted for by changes in actin-myosin separation, contributions by other factors cannot be excluded. Recently, a role for the giant elastic protein titin has been suggested (cardiac titin ~ 2500 kDa). Titin, which extends from the Z line to the M line, accounts for most of the elasticity of striated muscle fibers. The elasticity of titin is mainly a function of immunoglobulin-like domains lying in the I band segment of the molecule. Cazorla et al. (4) reported that in skinned cardiac myocytes the Ca²⁺ sensitivity is correlated with passive tension rather than sarcomere length. Moreover, degradation of titin by mild trypsin treatment caused an ~50% reduction in the change in pCa₅₀ produced by a given length change. A role for titin is plausible inasmuch as it is known to interact with thin filament proteins. However, in experiments in which correction was made for interfilament spacing (6), an independent effect of titin on Ca²⁺ sensitivity was not seen (Fig. 2). Confirmation of this finding in other types of skinned myocyte preparation is needed. One would also like to be able to relate Ca²⁺ sensitivity to the actual actin-myosin separation, as measured by X-ray diffraction, rather than the more crude measurement of fiber diameter. Additional studies along these lines may be very informative.

	Summary

Top Introduction The response of cardiac... Length-dependent Ca2+... Thin filament activation Strong-binding cross-bridges and... Length vs. width Length-dependent activation and... Problems for future... Summary References

 
The classic Frank-Starling relationship of the intact heart requires that the myocyte contain a length-sensing mechanism that adjusts the activity of the cross-bridges to the volume of blood in the relaxed ventricle. There is now a consensus that a length dependence of myofilament Ca²⁺ sensitivity is a key component of this mechanism. The Ca²⁺ sensitivity is a function of the level of myosin-mediated activation of the thin filament. The latter can be modulated by length-dependent variations in the lateral spacing between the actin and myosin filaments. Further studies are needed to identify the signaling pathways that link cross-bridge attachment and regulatory protein function.

	Acknowledgments

 
Because of editorial restrictions, many important contributions could not be cited. See Refs. 7 and 14 for a more comprehensive list of recent papers in this field.

Work in our laboratory has been supported by the National Institutes of Health and the American Heart Association, Mid-Atlantic Affiliate.

	References

Top Introduction The response of cardiac... Length-dependent Ca2+... Thin filament activation Strong-binding cross-bridges and... Length vs. width Length-dependent activation and... Problems for future... Summary References

 

1. Allen DG and Kentish JC. The cellular basis of the length-tension relation in cardiac muscle. J Mol Cell Cardiol 17: 821–840, 1985.[ISI][Medline]
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3. Arteaga GM, Palmiter KA, Leiden JM, and Solaro RJ. Attenuation of length-dependence of calcium activation in myofilaments of transgenic mouse hearts expressing slow skeletal troponin I. J Physiol (Lond) 526: 541–549, 2000.[Abstract/Free Full Text]
4. Cazorla O, Vassort G, Garnier D, and Le Guennec JY. Length modulation of active force in rat cardiac myocytes: is titin the sensor? J Mol Cell Cardiol 31: 1215–1227, 1999.[ISI][Medline]
5. Fitzsimons DP and Moss RL. Strong binding of myosin modulates length-dependent Ca²⁺ activation of rat ventricular myocytes. Circ Res 83: 602–607, 1998.[Abstract/Free Full Text]
6. Fuchs F and Wang Y-P. Sarcomere length versus interfilament spacing as determinants of cardiac myofilament Ca²⁺ sensitivity and Ca²⁺ binding. J Mol Cell Cardiol 28: 1375–1383, 1996.[ISI][Medline]
7. Gordon AM, Homsher E, and Regnier M. Regulation of contraction in striated muscle. Physiol Rev 80: 853–924, 2000.[Abstract/Free Full Text]
8. Head JG, Ritchie MD, and Geeves MA. Characterization of the equilibrium between blocked and closed states of muscle thin filaments. Eur J Biochem 227: 694–699, 1995.[ISI][Medline]
9. Hibberd MG and Jewell BR. Calcium and length-dependent force production in rat ventricular muscle. J Physiol (Lond) 329: 527–540, 1982.[Abstract/Free Full Text]
10. Hofmann PA and Fuchs F. Evidence for a force-dependent component of calcium binding to cardiac troponin C. Am J Physiol Cell Physiol 253: C541–C546, 1987.[Abstract/Free Full Text]
11. Lehrer SS and Geeves MA. The muscle thin filament as a classical cooperative/allosteric regulatory system. J Mol Biol 277: 1081–1089. 1988.
12. McDonald KS and Moss RL. Osmotic compression of single cardiac myocytes eliminates the reduction in Ca²⁺ sensitivity of tension at short sarcomere length. Circ Res 77: 199–205, 1995.[Abstract/Free Full Text]
13. Smith SH and Fuchs F. Effect of ionic strength on length-dependent Ca²⁺ activation in skinned cardiac muscle. J Mol Cell Cardiol 31: 2115–2125, 1999.[ISI][Medline]
14. Solaro RJ and Rarick HM. Troponin and tropomyosin: proteins that switch on and tune in the activity of cardiac myofilaments. Circ Res 83: 471–480, 1998.[Abstract/Free Full Text]
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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (36) Citing Articles via Google Scholar Google Scholar Articles by Fuchs, F. Articles by Smith, S. H. Search for Related Content PubMed PubMed Citation Articles by Fuchs, F. Articles by Smith, S. H.