Positive cardiac inotrope omecamtiv mecarbil activates muscle despite suppressing the myosin working stroke

Michael S Woody,Yale E Goldman,Michael J Greenberg,Bipasha Barua,E Michael Ostap,Donald A Winkelmann

doi:10.1038/s41467-018-06193-2

Abstract

Omecamtiv mecarbil (OM) is a positive cardiac inotrope in phase-3 clinical trials for treatment of heart failure. Although initially described as a direct myosin activator, subsequent studies are at odds with this description and do not explain OM-mediated increases in cardiac performance. Here we show, via single-molecule, biophysical experiments on cardiac myosin, that OM suppresses myosin’s working stroke and prolongs actomyosin attachment 5-fold, which explains inhibitory actions of the drug observed in vitro. OM also causes the actin-detachment rate to become independent of both applied load and ATP concentration. Surprisingly, increased myocardial force output in the presence of OM can be explained by cooperative thin-filament activation by OM-inhibited myosin molecules. Selective suppression of myosin is an unanticipated route to muscle activation that may guide future development of therapeutic drugs.

Highlights

Omecamtiv mecarbil (OM) is a positive cardiac inotrope in phase-3 clinical trials for treatment of heart failure
A single actin filament suspended between two optically trapped polystyrene beads is brought into proximity with a single myosin molecule adsorbed to a pedestal bead, which is anchored to the coverslip surface[15,16]
Single myosin molecules bind and displace the dumbbell when it is near the pedestal, and binding events are detected by analysis of the covariance of the bead position fluctuations[17,18]

Summary

Introduction

Omecamtiv mecarbil (OM) is a positive cardiac inotrope in phase-3 clinical trials for treatment of heart failure. Subsequent studies confirmed that OM increases the rate of phosphate release[6,7]; it was shown that OM inhibits the velocity of actin gliding in the in vitro motility assay at all concentrations tested[6,8,9,10] and reduces the rate of tension development and relaxation in myocytes at micromolar concentrations[1,9,11,12,13] These phenomena, along with observations of decreased isometric force in fully activated cardiomyocytes[11,14], are inconsistent with the originally proposed model for OM-activation of myosin in muscle. The results point to a mode of muscle activation by the selective modulation of a sub-population of myosin molecules

Methods

Results

Conclusion