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

William A. Kronert, Kaylyn M. Bell, Meera C. Viswanathan, Girish C. Melkani, Adriana S. Trujillo, Alice Huang, Anju Melkani, Anthony Ross Cammarato, Douglas M. Swank, Sanford I. Bernstein

Research output: Contribution to journalArticle

Abstract

K146N is a dominant mutation in human b-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.

Original languageEnglish (US)
Article numbere38064
JournaleLife
Volume7
DOIs
StatePublished - Aug 13 2018

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Hypertrophic Cardiomyopathy
Myosins
Drosophila
Muscle
Muscles
Mutation
Actins
Cardiac Myosins
Sarcomeres
Myosin Heavy Chains
Mechanics
Adenosine Triphosphatases
Rate constants
Assays
Screening
Alleles
Phenotype

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

Cite this

Kronert, W. A., Bell, K. M., Viswanathan, M. C., Melkani, G. C., Trujillo, A. S., Huang, A., ... Bernstein, S. I. (2018). Prolonged cross-bridge binding triggers muscle dysfunction in a drosophila model of myosin-based hypertrophic cardiomyopathy. eLife, 7, [e38064]. https://doi.org/10.7554/eLife.38064

Prolonged cross-bridge binding triggers muscle dysfunction in a drosophila model of myosin-based hypertrophic cardiomyopathy. / Kronert, William A.; Bell, Kaylyn M.; Viswanathan, Meera C.; Melkani, Girish C.; Trujillo, Adriana S.; Huang, Alice; Melkani, Anju; Cammarato, Anthony Ross; Swank, Douglas M.; Bernstein, Sanford I.

In: eLife, Vol. 7, e38064, 13.08.2018.

Research output: Contribution to journalArticle

Kronert, WA, Bell, KM, Viswanathan, MC, Melkani, GC, Trujillo, AS, Huang, A, Melkani, A, Cammarato, AR, Swank, DM & Bernstein, SI 2018, 'Prolonged cross-bridge binding triggers muscle dysfunction in a drosophila model of myosin-based hypertrophic cardiomyopathy', eLife, vol. 7, e38064. https://doi.org/10.7554/eLife.38064
Kronert, William A. ; Bell, Kaylyn M. ; Viswanathan, Meera C. ; Melkani, Girish C. ; Trujillo, Adriana S. ; Huang, Alice ; Melkani, Anju ; Cammarato, Anthony Ross ; Swank, Douglas M. ; Bernstein, Sanford I. / Prolonged cross-bridge binding triggers muscle dysfunction in a drosophila model of myosin-based hypertrophic cardiomyopathy. In: eLife. 2018 ; Vol. 7.
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