To lie or not to lie: Super-relaxing with myosins.

Suman Nag,Darshan V Trivedi

doi:10.7554/elife.63703

Abstract

Since the discovery of muscle in the 19th century, myosins as molecular motors have been extensively studied. However, in the last decade, a new functional super-relaxed (SRX) state of myosin has been discovered, which has a 10-fold slower ATP turnover rate than the already-known non-actin-bound, disordered relaxed (DRX) state. These two states are in dynamic equilibrium under resting muscle conditions and are thought to be significant contributors to adaptive thermogenesis in skeletal muscle and can act as a reserve pool that may be recruited when there is a sustained demand for increased cardiac muscle power. This report provides an evolutionary perspective of how striated muscle contraction is regulated by modulating this myosin DRX↔SRX state equilibrium. We further discuss this equilibrium with respect to different physiological and pathophysiological perturbations, including insults causing hypertrophic cardiomyopathy, and small-molecule effectors that modulate muscle contractility in diseased pathology.

Highlights

Enzymes, an epitome of exquisite evolutionary design, can modulate their activity by intricate conformational changes induced by upstream events that reflect the dynamic requirements of a cell
In the cardiac and skeletal muscles, myosins form a part of the thick filament, which slides across actin-containing thin filaments, thereby producing the necessary force required for muscle contractility
SRX state was significantly depopulated in these mice, but there were no significant changes in the lifetimes of the SRX or disordered relaxed (DRX) states. These observations underline the importance of light chains in modulating the SRX state of myosin. These investigations show that single-point mutations across the myosin molecule, either naturally occurring which causes hypertrophic cardiomyopathy (HCM) or those engineered in the laboratory, affect the DRX$SRX state equilibrium, thereby emphasizing the evolutionary importance of residues in different domains of the myosin molecule that directly contribute to the energetic fine-tunings of the muscle

Summary

Introduction

An epitome of exquisite evolutionary design, can modulate their activity by intricate conformational changes induced by upstream events that reflect the dynamic requirements of a cell. It is only recently that a study has reported that Ca2+ and not Mg2+ binding to reconstituted porcine cardiac myosin filaments depopulated the myosin SRX state, thereby proposing Ca2+-mediated activation of the thick filament as an additional regulation of the vertebrate muscle (Sa et al, 2019).

Results

Conclusion