Small molecule drugs to improve sarcomere function in those with acquired and inherited myopathies

Abstract

Muscle weakness is a hallmark of inherited or acquired myopathies. It is a major cause of functional impairment and can advance to life threatening respiratory insufficiency. During the past decade, several small molecule drugs that improve the contractility of skeletal muscle fibers have been developed. In this review we provide an overview of the available literature and the mechanisms of action of small molecule drugs that modulate the contractility of sarcomeres, the smallest contractile units in striated muscle, by acting on myosin and troponin. We also discuss their use in the treatment of skeletal myopathies. The first of three classes of drugs discussed here increase contractility by decreasing the dissociation rate of calcium from troponin and thereby sensitizing the muscle to calcium. The second two classes of drugs directly act on myosin and stimulate or inhibit the kinetics of myosin-actin interactions, which may be useful in patients with muscle weakness or stiffness.

Tail Length and E525K Dilated Cardiomyopathy Mutant Alter Human β-Cardiac Myosin Super-Relaxed State

“…HCM linked mutations have been shown to destabilize the IHM/SRX state, allowing more myosin heads to interact with the thin filament, offering a mechanistic explanation for the hyper-contractile HCM phenotype [15][16][17] . In fact, Mavacamten, an FDA approved, small-molecule therapeutic for HCM patients 18 , targets M2β and restores normal contractility by increasing the probability of the myosin IHM/SRX state.…”

“…HCM linked mutations have been shown to destabilize the IHM/SRX state, allowing more myosin heads to interact with the thin filament, offering a mechanistic explanation for the hyper-contractile HCM phenotype 15-17 . In fact, Mavacamten, an FDA approved, small-molecule therapeutic for HCM patients 18 , targets M2β and restores normal contractility by increasing the probability of the myosin IHM/SRX state. Accordingly, we hypothesize that the hypo-contractile phenotype observed with DCM-associated M2β mutations arises from enhanced stabilization of the IHM/SRX state, reducing the number of myosin motors available to generate the power required for normal cardiac output 8 (Fig.…”