IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v9y2018i1d10.1038_s41467-018-06193-2.html
   My bibliography  Save this article

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

Author

Listed:
  • Michael S. Woody

    (University of Pennsylvania)

  • Michael J. Greenberg

    (University of Pennsylvania
    Washington University in Saint Louis)

  • Bipasha Barua

    (Rutgers University)

  • Donald A. Winkelmann

    (Rutgers University)

  • Yale E. Goldman

    (University of Pennsylvania)

  • E. Michael Ostap

    (University of Pennsylvania)

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.

Suggested Citation

  • Michael S. Woody & Michael J. Greenberg & Bipasha Barua & Donald A. Winkelmann & Yale E. Goldman & E. Michael Ostap, 2018. "Positive cardiac inotrope omecamtiv mecarbil activates muscle despite suppressing the myosin working stroke," Nature Communications, Nature, vol. 9(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-06193-2
    DOI: 10.1038/s41467-018-06193-2
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-018-06193-2
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-018-06193-2?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    Cited by:

    1. Priyanka Parijat & Seetharamaiah Attili & Zoe Hoare & Michael Shattock & Victor Kenyon & Thomas Kampourakis, 2023. "Discovery of a novel cardiac-specific myosin modulator using artificial intelligence-based virtual screening," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    2. Daniel Auguin & Julien Robert-Paganin & Stéphane Réty & Carlos Kikuti & Amandine David & Gabriele Theumer & Arndt W. Schmidt & Hans-Joachim Knölker & Anne Houdusse, 2024. "Omecamtiv mecarbil and Mavacamten target the same myosin pocket despite opposite effects in heart contraction," Nature Communications, Nature, vol. 15(1), pages 1-14, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-06193-2. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    We have no bibliographic references for this item. You can help adding them by using this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.