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

Michael S. Woody, Michael J. Greenberg, Bipasha Barua, Donald A. Winkelmann, Yale E. Goldman () and E. Michael Ostap ()
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Michael S. Woody: University of Pennsylvania
Michael J. Greenberg: University of Pennsylvania
Bipasha Barua: Rutgers University
Donald A. Winkelmann: Rutgers University
Yale E. Goldman: University of Pennsylvania
E. Michael Ostap: University of Pennsylvania

Nature Communications, 2018, vol. 9, issue 1, 1-11

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-06193-2

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