Effect of Cardiac Myosin Binding Protein-C on Mechanoenergetics in Mouse Myocardium

Palmer, Bradley M.; Noguchi, Teruo; Wang, Yuan; Heim, John R.; Alpert, Norman R.; Burgon, Patrick G.; Seidman, Christine E.; Seidman, Jonathan G.; Maughan, David W.; LeWinter, Martin M.

doi:10.1161/01.res.0000132744.08754.f2

Cited by 50 publications

(47 citation statements)

References 43 publications

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“…Several investigators have proposed that the reduced unloaded shortening velocity in fiber studies is the result of cMyBP-C functioning either as a tether restricting myosin's interactions with actin [15,29,[43][44][45] and/or imparting a viscous load to thick-thin filament sliding [46]. Our data would indicate that neither of these mechanisms can account for the functional effects observed with cMyBP-C in this study.…”

Section: Discussionmentioning

confidence: 50%

Cardiac myosin binding protein-C modulates actomyosin binding and kinetics in the in vitro motility assay

Saber

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Warshaw

et al. 2008

Journal of Molecular and Cellular Cardiology

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The modulatory role of whole cardiac myosin binding protein-C (cMyBP-C) on myosin force and motion generation was assessed in an in vitro motility assay. The presence of cMyBP-C at an approximate molar ratio of cMyBP-C to whole myosin of 1:2, resulted in a 25% reduction in thin filament velocity (P<0.002) with no effect on relative isometric force under maximally activated conditions (pCa 5). Cardiac MyBP-C was capable of inhibiting actin filament velocity in a concentration-dependent manner using either whole myosin, HMM or S1, indicating that the cMyBP-C does not have to bind to myosin LMM or S2 subdomains to exert its effect. The reduction in velocity by cMyBP-C was independent of changes in ionic strength or excess inorganic phosphate. Cosedimentation experiments demonstrated S1 binding to actin is reduced as a function of cMyBP-C concentration in the presence of ATP. In contrast, S1 avidly bound to actin in the absence of ATP and limited cMyBP-C binding, indicating that cMyBP-C and S1 compete for actin binding in an ATP-dependent fashion. However, based on the relationship between thin filament velocity and filament length, the cMyBP-C induced reduction in velocity was independent of the number of crossbridges interacting with the thin filament. In conclusion, the effects of cMyBP-C on velocity and force at both maximal and submaximal activation demonstrate that cMyBP-C does not solely act as a tether between the myosin S2 and LMM subdomains but likely affects both the kinetics and recruitment of myosin cross-bridges through its direct interaction with actin and/or myosin head.

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Section: Discussionmentioning

confidence: 50%

Cardiac myosin binding protein-C modulates actomyosin binding and kinetics in the in vitro motility assay

Saber

Begin

Warshaw

et al. 2008

Journal of Molecular and Cellular Cardiology

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“…This interpretation is well compatible with 2 recent studies on skinned myocyte Ca 2ϩ sensitivity. Whereas earlier studies had reported mixed effects of extraction or ablation of cMyBP-C on Ca 2ϩ sensitivity in skinned preparations (increase, 31,32 no change, 40 or decrease 25,29 ), the newer data on skinned KO preparations demonstrated a lower Hill coefficient of the pCa-force relation, indicating a reduced cooperativity of the myofilament activation. 27,31 A potential mechanistic explanation for this finding comes from a recent study describing a radial displacement of cross-bridges away from the thick filament in the absence of Ca 2ϩ .…”

Section: Discussionmentioning

confidence: 83%

Cardiac Myosin-Binding Protein C Is Required for Complete Relaxation in Intact Myocytes

Pohlmann

Kröger

Vignier

et al. 2007

Circulation Research

119

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Abstract-The role of cardiac myosin-binding protein C (cMyBP-C) in cardiac contraction is still not fully resolved.Experimental ablation of cMyBP-C by various means resulted in inconsistent changes in Ca 2ϩ sensitivity and increased velocity of force of skinned preparations. To evaluate how these effects are integrated in an intact, living myocyte context, we investigated consequences of cMyBP-C ablation in ventricular myocytes and left atria from cMyBP-C knock-out (KO) mice compared with wild-type (WT). At 6 weeks, KO myocytes exhibited mild hypertrophy that became more pronounced by 30 weeks. Isolated cells from KO exhibited markedly lower diastolic sarcomere length (SL) without change in diastolic Ca 2ϩ . The lower SL in KO was partly abolished by the actin-myosin ATPase inhibitors 2,3-butanedione monoxime or blebbistatin, indicating residual actin-myosin interaction in diastole. The relationship between cytosolic Ca 2ϩ and SL showed that KO cells started to contract at lower Ca 2ϩ without reaching a higher maximum, yielding a smaller area of the phase-plane diagram. Both sarcomere shortening and Ca 2ϩ transient were prolonged in KO. Isolated KO left atria exhibited a marked increase in sensitivity to external Ca 2ϩ and, in contrast to WT, continued to develop twitch force at low micromolar Ca 2ϩ . Taken together, the main consequence of cMyBP-C ablation was a defect in diastolic relaxation and a smaller dynamic range of cell shortening, both of which likely result from the increased myofilament Ca 2ϩ sensitivity. Our findings indicate that cMyBP-C functions as a restraint on myosin-actin interaction at low Ca 2ϩ and short SL to allow complete relaxation during diastole. (Circ Res. 2007;101:928-938.)

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“…Thus, it appears that ablation or phosphorylation of cMyBP-C result in similar accelerations in the rates of cross-bridge detachment, perhaps because of a decrease in a putative internal viscous load normally provided by cMyBP-C, which acts to slow the speed of shortening. 40 PKA phosphorylation of WT and cTnI ala2 myocardium also increased the number of cross-bridges that detach following stretch, which is evident in more negative values of P 2 ( Figure 3). Because more negative values of P 2 have been interpreted as indicating greater reversal of force-producing steps in response to stretch, 41 cMyBP-C phosphorylation appears to accelerate cross-bridge reverse transitions from strongly bound to weakly bound states so that force relaxation is accelerated.…”

Section: Discussionmentioning

confidence: 90%

Differential Roles of Cardiac Myosin-Binding Protein C and Cardiac Troponin I in the Myofibrillar Force Responses to Protein Kinase A Phosphorylation

Stelzer

Patel

Walker

et al. 2007

Circulation Research

152

194

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Abstract-The heart is remarkably adaptable in its ability to vary its function to meet the changing demands of the circulatory system. During times of physiological stress, cardiac output increases in response to increased sympathetic activity, which results in protein kinase A (PKA)-mediated phosphorylations of the myofilament proteins cardiac troponin (cTn)I and cardiac myosin-binding protein (cMyBP)-C. Despite the importance of this mechanism, little is known about the relative contributions of cTnI and cMyBP-C phosphorylation to increased cardiac contractility. Using engineered mouse lines either lacking cMyBP-C (cMyBP-C Ϫ/Ϫ ) or expressing a non-PKA phosphorylatable cTnI (cTnI ala2 ), or both (cMyBP-C Ϫ/Ϫ /cTnI ala2 ), we investigated the roles of cTnI and cMyBP-C phosphorylation in the regulation of the stretch-activation response. PKA treatment of wild-type and cTnI ala2 skinned ventricular myocardium accelerated stretch activation such that the response was indistinguishable from stretch activation of cMyBP-C Ϫ/Ϫ or cMyBP-C Ϫ/Ϫ /cTnI ala2 myocardium; however, PKA had no effect on stretch activation in cMyBP-C Ϫ/Ϫ or cMyBP-C Ϫ/Ϫ /cTnI ala2 myocardium. These results indicate that the acceleration of stretch activation in wild-type and cTnI ala2 myocardium is caused by phosphorylation of cMyBP-C and not cTnI. We conclude that the primary effect of PKA phosphorylation of cTnI is reduced Ca 2ϩ sensitivity of force, whereas phosphorylation of cMyBP-C accelerates the kinetics of force development. These results predict that PKA phosphorylation of myofibrillar proteins in living myocardium contributes to accelerated relaxation in diastole and increased rates of force development in systole. (Circ Res. 2007;101:503-511.) Key Words: cross-bridge kinetics Ⅲ ␤-adrenergic agonists Ⅲ positive inotropy Ⅲ contractile protein function E nhanced cardiac contractile performance in response to increased circulatory demands is achieved in part through positive inotropy and lusitropy in response to increased sympathetic tone, resulting in increased stroke work during systole and earlier relaxation to optimize diastolic filling. Underscoring the importance of ␤-adrenergic stimulation in myocardial function, chronic hyperactivation of ␤-adrenergic pathways 1 or blunting of the ␤-adrenergic response 2 has been implicated in end-stage human heart failure.At the level of the myofilament, the force at a given level of Ca 2ϩ and the rate at which force is developed depend on properties that are intrinsic to the contractile proteins, such as protein isoforms, and on factors that affect protein function, such as phosphorylation status. ␤-Adrenergic stimulation effects on the heart are mediated via cAMP activation of protein kinase A (PKA), which in the myofilament, principally targets the thin filament protein cTnI and the thick filament protein cMyBP-C. In skinned myocardium, phosphorylation of cTnI and cMyBP-C is associated with increased rates of cross-bridge cycling and decreased Ca 2ϩ sensitivity of force (reviewed elsewhere 3,4 ...

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Effect of Cardiac Myosin Binding Protein-C on Mechanoenergetics in Mouse Myocardium

Cited by 50 publications

References 43 publications

Cardiac myosin binding protein-C modulates actomyosin binding and kinetics in the in vitro motility assay

Cardiac myosin binding protein-C modulates actomyosin binding and kinetics in the in vitro motility assay

Cardiac Myosin-Binding Protein C Is Required for Complete Relaxation in Intact Myocytes

Differential Roles of Cardiac Myosin-Binding Protein C and Cardiac Troponin I in the Myofibrillar Force Responses to Protein Kinase A Phosphorylation

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