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Prolonged cross-bridge binding triggers muscle dysfunction in a fly model of myosin-based hypertrophic cardiomyopathy

  1. William A Kronert
  2. Kaylyn M Bell
  3. Meera C Viswanathan
  4. Girish C Melkani
  5. Adriana S Trujillo
  6. Alice Huang
  7. Anju Melkani
  8. Anthony Cammarato
  9. Douglas M Swank  Is a corresponding author
  10. Sanford I Bernstein  Is a corresponding author
  1. San Diego State University, United States
  2. Rensselaer Polytechnic Institute, United States
  3. Johns Hopkins University, United States
Research Article
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Cite this article as: eLife 2018;7:e38064 doi: 10.7554/eLife.38064

Abstract

K146N is a dominant mutation in human β-cardiac myosin heavy chain, which causes hypertrophic cardiomyopathy. We examined how Drosophila muscle responds to this mutation and integratively analyzed the biochemical, physiological and mechanical foundations of the disease. ATPase assays, actin motility, and indirect flight muscle mechanics suggest at least two rate constants of the cross-bridge cycle are altered by the mutation: increased myosin attachment to actin and decreased detachment, yielding prolonged binding. This increases isometric force generation, but also resistive force and work absorption during cyclical contractions, resulting in decreased work, power output, flight ability and degeneration of flight muscle sarcomere morphology. Consistent with prolonged cross-bridge binding serving as the mechanistic basis of the disease and with human phenotypes, 146N/+ hearts are hypercontractile with increased tension generation periods, decreased diastolic/systolic diameters and myofibrillar disarray. This suggests that screening mutated Drosophila hearts could rapidly identify hypertrophic cardiomyopathy alleles and treatments.

Article and author information

Author details

  1. William A Kronert

    Department of Biology, San Diego State University, San Diego, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Kaylyn M Bell

    Department of Biological Sciences, Rensselaer Polytechnic Institute, Troy, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Meera C Viswanathan

    Department of Medicine, Johns Hopkins University, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Girish C Melkani

    Department of Biology, San Diego State University, San Diego, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Adriana S Trujillo

    Department of Biology, San Diego State University, San Diego, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Alice Huang

    Department of Biological Sciences, Rensselaer Polytechnic Institute, Troy, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Anju Melkani

    Department of Biology, San Diego State University, San Diego, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Anthony Cammarato

    Department of Medicine, Johns Hopkins University, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Douglas M Swank

    Department of Biological Sciences, Rensselaer Polytechnic Institute, Troy, United States
    For correspondence
    swankd@rpi.edu
    Competing interests
    The authors declare that no competing interests exist.
  10. Sanford I Bernstein

    Department of Biology, San Diego State University, San Diego, United States
    For correspondence
    sbernstein@sdsu.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7094-5390

Funding

National Institutes of Health (R37GM032443)

  • Sanford I Bernstein

National Institutes of Health (R01HL124091)

  • Anthony Cammarato

National Institutes of Health (R01AR064274)

  • Douglas M Swank

Rees-Steely Research Foundation (Graduate Student Fellowship)

  • Adriana S Trujillo

The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Reviewing Editor

  1. Lee Sweeney

Publication history

  1. Received: May 3, 2018
  2. Accepted: August 10, 2018
  3. Accepted Manuscript published: August 13, 2018 (version 1)
  4. Version of Record published: September 17, 2018 (version 2)

Copyright

© 2018, Kronert et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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