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

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

doi:10.7554/elife.38064

William A Kronert, Douglas M Swank + Show 8 more

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https://doi.org/10.7554/elife.38064

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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.

Highlights

Heritable hypertrophic cardiomyopathy (HCM) is a leading cause of death among young adults, competitive athletes
We determined the location and interactions for the amino acid residue corresponding to human K146, which in its mutant form (K146N) causes HCM
The Drosophila indirect flight muscle (IFM) myosin heavy chain sequence was modeled onto the scallop muscle myosin II crystal structure during the pre-power stroke state (PDB 1QVI) and the actin-detached post-power stroke state (PDB 1KK8) (Figure 1A and B)

Summary

Introduction

Heritable hypertrophic cardiomyopathy (HCM) is a leading cause of death among young adults, competitive athletes. This heterogeneous and complex disease typically involves asymmetric growth of the heart, interventricular septum thickening, disorganized cellular architecture, diastolic dysfunction, arrhythmias, and an increased risk of sudden cardiac death (Davis et al, 2016; Maron, 2002; Maron and Maron, 2013; Masarone et al, 2018). The over-active contractile apparatus can prolong mechanical tension, which apparently initiates hypertrophy via activation of specific signaling cascades that regulate heart growth (Davis et al, 2016).

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