Poorly Understood Aspects of Striated Muscle Contraction

Abstract

Muscle contraction results from cyclic interactions between the contractile proteins myosin and actin, driven by the turnover of adenosine triphosphate (ATP). Despite intense studies, several molecular events in the contraction process are poorly understood, including the relationship between force-generation and phosphate-release in the ATP-turnover. Different aspects of the force-generating transition are reflected in the changes in tension development by muscle cells, myofibrils and single molecules upon changes in temperature, altered phosphate concentration, or length perturbations. It has been notoriously difficult to explain all these events within a given theoretical framework and to unequivocally correlate observed events with the atomic structures of the myosin motor. Other incompletely understood issues include the role of the two heads of myosin II and structural changes in the actin filaments as well as the importance of the three-dimensional order. We here review these issues in relation to controversies regarding basic physiological properties of striated muscle. We also briefly consider actomyosin mutation effects in cardiac and skeletal muscle function and the possibility to treat these defects by drugs.

Actomyosin based contraction: one mechanokinetic model from single molecules to muscle?

“…This is important (e.g. Malnasi-Csizmadia and Kovacs 2010; Månsson et al 2015) in order for a model to be useful for connecting biochemical transitions to mechanical events in fundamental studies and for elucidating effects of disease-causing mutations and effects of drugs. A separate Pi-release seems essential to account for structural and biochemical findings (Llinas et al 2015; Sweeney and Houdusse 2010).…”

“…It is well-known that contraction of striated muscle (skeletal muscle and heart) results from interactions, driven by ATP-turnover, between myosin and actin (Månsson et al 2015). The arrangement of these proteins in large ordered ensembles, sarcomeres, in striated muscle ensures highly optimized function as indicated by convergent evolution in organisms as distant as cnidarians (e.g.…”

“…jellyfish) and mammals (Steinmetz et al 2012). Despite intense studies, the basis for the high level of perfection of the ordered system remains poorly understood (Batters et al 2014; Månsson et al 2015). This fact is not only of fundamental importance.…”

“…cardiomyopathies (Ferrantini et al 2009; Frey et al 2012; Green et al 2016; Marston 2011; Spudich 2014; Teekakirikul et al 2012), a leading cause of sudden death in young people, and heart failure, a leading cause of hospitalization and mortality where myosin-active drugs may be useful (Malik et al 2011; Teerlink et al 2011). One reason for remaining knowledge gaps is the difficulty to integrate experimental results as well as key concepts, from studies using different techniques and hierarchical scales ranging from single molecules over small ensembles to muscle (Baker et al 2002; Månsson et al 2015; Walcott et al 2012). One tool that would be valuable in this regard is a mathematical model that bridges the gap while being both simple enough to effectively aid data interpretation and sufficiently detailed to incorporate biochemical actomyosin states that are critical for function.…”

A model of cardiac contraction based on novel measurements of tension development in human cardiomyocytes

“…Thin filaments are composed of actin, tropomyosin, and troponins, including troponin C and troponin I. Thick filaments are made up of myosin crossbridges [18,60,61,5,46]. Active tension is generated by myosin crossbridges attaching to binding sites on actin on the thin filament, and then performing a powerstroke.…”