4.8 Article

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

Journal

NATURE COMMUNICATIONS
Volume 9, Issue -, Pages -

Publisher

NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-018-06193-2

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Funding

  1. Center for Engineering MechanoBiology NSF Science and Technology Center [CMMI: 15-48571]
  2. National Institutes of Health [R35-GM118139, P01-GM087253, R01-HL133863, R00 HL123623]
  3. National Science Foundation

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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.

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