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.
journal_name
Elifejournal_title
eLifeauthors
Kronert WA,Bell KM,Viswanathan MC,Melkani GC,Trujillo AS,Huang A,Melkani A,Cammarato A,Swank DM,Bernstein SIdoi
10.7554/eLife.38064subject
Has Abstractpub_date
2018-08-13 00:00:00issn
2050-084Xpii
38064journal_volume
7pub_type
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