Prolonged cross-bridge binding triggers muscle dysfunction in a fly model of myosin-based hypertrophic cardiomyopathy
- San Diego State University, United States
- Rensselaer Polytechnic Institute, United States
- Johns Hopkins University, United States
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.
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Data generated or analysed during this study are included in the manuscript and supporting files.
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Author details
Sanford I Bernstein
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.
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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Prolonged cross-bridge binding triggers muscle dysfunction in a fly model of myosin-based hypertrophic cardiomyopathy
eLife 7:e38064.
https://doi.org/10.7554/eLife.38064
