Myosin dilated cardiomyopathy mutation S532P disrupts actomyosin interactions, leading to altered muscle kinetics, reduced locomotion, and cardiac dilation in Drosophila

Trujillo, Adriana S.; Hsu, Karen H.; Puthawala, Joy; Viswanathan, Meera C.; Loya, Amy; Irving, Thomas C.; Cammarato, Anthony; Swank, Douglas M.; Bernstein, Sanford I.

doi:10.1091/mbc.e21-02-0088

Myosin dilated cardiomyopathy mutation S532P disrupts actomyosin interactions, leading to altered muscle kinetics, reduced locomotion, and cardiac dilation in Drosophila

Journal Article · Thu Aug 19 00:00:00 EDT 2021 · Molecular Biology of the Cell

DOI:https://doi.org/10.1091/mbc.e21-02-0088· OSTI ID:1819326

Trujillo, Adriana S. ^[1]; Hsu, Karen H. ^[1]; Puthawala, Joy ^[2]; Viswanathan, Meera C. ^[3]; Loya, Amy ^[2]; Irving, Thomas C. ^[4]; Cammarato, Anthony ^[3]; Swank, Douglas M. ^[2]; Bernstein, Sanford I. ^[1]

San Diego State Univ., CA (United States)
Rensselaer Polytechnic Inst., Troy, NY (United States)
Johns Hopkins Univ., Baltimore, MD (United States)
Illinois Inst. of Technology, Chicago, IL (United States)

Dilated cardiomyopathy (DCM), a life-threatening disease characterized by pathological heart enlargement, can be caused by myosin mutations that reduce contractile function. To better define the mechanistic basis of this disease, we employed the powerful genetic and integrative approaches available in Drosophila melanogaster. To this end, we generated and analyzed the first fly model of human myosin–induced DCM. The model reproduces the S532P human β-cardiac myosin heavy chain DCM mutation, which is located within an actin-binding region of the motor domain. In concordance with the mutation’s location at the actomyosin interface, steady-state ATPase and muscle mechanics experiments revealed that the S532P mutation reduces the rates of actin-dependent ATPase activity and actin binding and increases the rate of actin detachment. The depressed function of this myosin form reduces the number of cross-bridges during active wing beating, the power output of indirect flight muscles, and flight ability. Further, S532P mutant hearts exhibit cardiac dilation that is mutant gene dose–dependent. Our study shows that Drosophila can faithfully model various aspects of human DCM phenotypes and suggests that impaired actomyosin interactions in S532P myosin induce contractile deficits that trigger the disease.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: National Institutes of Health (NIH); USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities Division

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 1819326

Journal Information:: Molecular Biology of the Cell, Journal Name: Molecular Biology of the Cell Journal Issue: 18 Vol. 32; ISSN 1059-1524

Publisher:: American Society for Cell BiologyCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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