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

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.

Keywords: Hypertrophic cardiomyopathy; Interacting heads motif; Mavacamten; Muscle Contraction; Myosin; Super-relaxed state; biochemistry; chemical biology; molecular biophysics; structural biology.

Figure 1.. Schematic representation of the possible different functional states of myosin.

(a) Highlighted in green are actin-bound myosins, which are most active and utilize maximum ATP. This myosin state is in equilibrium with an off-actin state, shown in orange, the DRX state of myosin, which has 100-fold less activity than the actin-interacting form. Myosins in the DRX state are in equilibrium with those in the SRX state, as shown in red, which has a further 10-fold less activity than the DRX state. The SRX state of myosin could be due to either a traditional IHM state or a non-IHM state. Actin is shown as gray globular domains, and the myosin thick-filament shaft is shown as a gray cylindrical rod. (b) Simulated energy (ATP) utilization by different myosin states is shown. The ATP turnover rate for the actin-bound myosin, DRX myosin, and SRX myosin was assumed to be 3 s⁻¹, 0.03 s⁻¹, and 0.003 s⁻¹, respectively. A standard deviation of 0.1 units was used to generate random Gaussian noise. The simulated curves were generated using the GraphPad Prism software.

Figure 2.. Schematic representation of the possible different functional states of myosin.

(a) Different states of myosins are arranged in the order of their energy utilization- actin-bound myosin in green, DRX myosin in orange, and SRX myosin in red. (b) Graphical representation of how different physiological, pathophysiological, and non-physiological perturbations, as listed, alter the myosin population in these three different states. The small blue arrows next to the different perturbations denote an increase of those parameters. The battery symbol in each box qualitatively resembles the energy saved by the system in each scenario.