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

Abstract

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.

Authors:
 [1];  [1];  [2];  [3];  [2];  [4];  [3];  [2];  [1]
+ Show Author Affiliations
  1. San Diego State Univ., CA (United States)
  2. Rensselaer Polytechnic Inst., Troy, NY (United States)
  3. Johns Hopkins Univ., Baltimore, MD (United States)
  4. Illinois Inst. of Technology, Chicago, IL (United States)
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities Division; National Institutes of Health (NIH)
OSTI Identifier:
1819326
Grant/Contract Number:  
AC02-06CH11357; P41 GM103622; F31HL128118; R37GM032443; R01HL124091
Resource Type:
Accepted Manuscript
Journal Name:
Molecular Biology of the Cell
Additional Journal Information:
Journal Volume: 32; Journal Issue: 18; Journal ID: ISSN 1059-1524
Publisher:
American Society for Cell Biology
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES

Citation Formats

Trujillo, Adriana S., Hsu, Karen H., Puthawala, Joy, Viswanathan, Meera C., Loya, Amy, Irving, Thomas C., Cammarato, Anthony, Swank, Douglas M., and Bernstein, Sanford I. Myosin dilated cardiomyopathy mutation S532P disrupts actomyosin interactions, leading to altered muscle kinetics, reduced locomotion, and cardiac dilation in Drosophila. United States: N. p., 2021. Web. doi:10.1091/mbc.e21-02-0088.
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Trujillo, Adriana S., Hsu, Karen H., Puthawala, Joy, Viswanathan, Meera C., Loya, Amy, Irving, Thomas C., Cammarato, Anthony, Swank, Douglas M., & Bernstein, Sanford I. Myosin dilated cardiomyopathy mutation S532P disrupts actomyosin interactions, leading to altered muscle kinetics, reduced locomotion, and cardiac dilation in Drosophila. United States. https://doi.org/10.1091/mbc.e21-02-0088
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Trujillo, Adriana S., Hsu, Karen H., Puthawala, Joy, Viswanathan, Meera C., Loya, Amy, Irving, Thomas C., Cammarato, Anthony, Swank, Douglas M., and Bernstein, Sanford I. Thu . "Myosin dilated cardiomyopathy mutation S532P disrupts actomyosin interactions, leading to altered muscle kinetics, reduced locomotion, and cardiac dilation in Drosophila". United States. https://doi.org/10.1091/mbc.e21-02-0088. https://www.osti.gov/servlets/purl/1819326.
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@article{osti_1819326,
title = {Myosin dilated cardiomyopathy mutation S532P disrupts actomyosin interactions, leading to altered muscle kinetics, reduced locomotion, and cardiac dilation in Drosophila},
author = {Trujillo, Adriana S. and Hsu, Karen H. and Puthawala, Joy and Viswanathan, Meera C. and Loya, Amy and Irving, Thomas C. and Cammarato, Anthony and Swank, Douglas M. and Bernstein, Sanford I.},
abstractNote = {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.},
doi = {10.1091/mbc.e21-02-0088},
journal = {Molecular Biology of the Cell},
number = 18,
volume = 32,
place = {United States},
year = {Thu Aug 19 00:00:00 EDT 2021},
month = {Thu Aug 19 00:00:00 EDT 2021}
}
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https://doi.org/10.1091/mbc.e21-02-0088
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