Myosin Crossbridge Activation of Cardiac Thin Filaments

Abstract

Abstract-At the level of the myofibrillar proteins, activation of myocardial contraction is thought to involve switch-like regulation of crossbridge binding to the thin filaments. A central feature of this view of regulation is that Ca 2ϩ binding to the low-affinity (Ϸ3 mol/L) site on troponin C alters the interactions of proteins in the thin filament regulatory strand, which leads to movement of tropomyosin from its blocking position on the thin filament and binding of crossbridges to actin. Although Ca 2ϩ binding is a critical step in initiating contraction, this event alone does not account for the activation dependence of contractile properties of myocardium. Instead, activation is a highly cooperative process in which initial crossbridge binding to the thin filaments recruits additional crossbridge binding to actin as well as increased Ca 2ϩ binding to troponin C. This review addresses possible roles of thin filament cooperativity in myocardium as a process that modulates the activation dependence of force and the rate of force development and also possible mechanisms by which cooperative signals are transmitted along the thick filament. Emerging evidence suggests that such mechanisms could contribute to the regulation of fundamental mechanical properties of myocardium and alterations in regulation that underlie contractile disorders in diseases such as cardiomyopathies.

Transgenic overexpression of ribonucleotide reductase improves cardiac performance

“…Heart disease is the leading cause of mortality and morbidity in the United States and has been rising dramatically around the world (37). Many cardiopathologies, as well as ischemia-reperfusion injury and myocardial infarct, result in reduced systolic function (1)(2)(3)(4). Whether heart failure results from infarction or other diseases that reduce systolic function, the most common treatment strategies are pharmacological therapies and/or surgery.…”

“…metabolism | inotropy | cross-bridge cycling A wide variety of cardiac pathologies such as myocardial infarct, dilated cardiomyopathy, and congestive heart failure involve reduced systolic function of ventricles that often results from altered ATP-mediated actin-myosin (cross-bridge) cycling (1)(2)(3)(4). The schematic shown in Fig.…”

Top-down high-resolution mass spectrometry of cardiac myosin binding protein C revealed that truncation alters protein phosphorylation state

“…C ardiac myosin binding protein C (cMyBP-C), located in the sarcomere's thick filament, plays an important role in the regulation of cardiac contraction and maintenance of myosin filament structure (1)(2)(3)(4)(5). Mutations in cMyBP-C are widely recognized as the most common cause of many heritable hypertrophic cardiomypathies in which the heart is hypertrophied, hypercontractile, and susceptible to electric and mechanic failure (6).…”

Myosin Transducer Mutations Differentially Affect Motor Function, Myofibril Structure, and the Performance of Skeletal and Cardiac Muscles

“…On activation, tropomyosin shifts positions in a stepwise manner away from these binding sites, first as a result of Ca 2ϩ binding to troponin and then by myosin cross-bridge binding to actin (McKillop and Geeves, 1993;Vibert et al, 1997;Poole et al, 2006). Initial cross-bridge binding to actin seems to have allosteric effects on thin filaments such that there is a spread of accessible myosin binding sites along the filaments leading to cooperative activation of contraction (reviewed by Tobacman, 1996;Gordon et al, 2000;Moss et al, 2004). Thus, both elevated Ca 2ϩ levels and cross-bridge binding are required for full activation.…”