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Title: Sarcomeric perturbations of myosin motors lead to dilated cardiomyopathy in genetically modified MYL2 mice

Abstract

Dilated cardiomyopathy (DCM) is a devastating heart disease that affects about 1 million people in the United States, but the underlying mechanisms remain poorly understood. In this study, we aimed to determine the biomechanical and structural causes of DCM in transgenic mice carrying a novel mutation in theMYL2gene, encoding the cardiac myosin regulatory light chain. Transgenic D94A (aspartic acid-to-alanine) mice were created and investigated by echocardiography and invasive hemodynamic and molecular structural and functional assessments. Consistent with the DCM phenotype, a significant reduction of the ejection fraction (EF) was observed in ~5- and ~12-mo-old male and female D94A lines compared with respective WT controls. Younger male D94A mice showed a more pronounced left ventricular (LV) chamber dilation compared with female counterparts, but both sexes of D94A lines developed DCM by 12 mo of age. The hypocontractile activity of D94A myosin motors resulted in the rightward shift of the force–pCa dependence and decreased actin-activated myosin ATPase activity. Consistent with a decreased Ca 2+sensitivity of contractile force, a small-angle X-ray diffraction study, performed in D94A fibers at submaximal Ca 2+concentrations, revealed repositioning of the D94A cross-bridge mass toward the thick-filament backbone supporting the hypocontractile state of D94A myosin motors. Our data suggestmore » that structural perturbations at the level of sarcomeres result in aberrant cardiomyocyte cytoarchitecture and lead to LV chamber dilation and decreased EF, manifesting in systolic dysfunction of D94A hearts. The D94A-induced development of DCM in mice closely follows the clinical phenotype and suggests thatMYL2may serve as a new therapeutic target for dilated cardiomyopathy.« less

Authors:
 [1];  [1];  [1];  [1];  [1];  [2];  [3]; ORCiD logo [1]
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  1. Univ. of Miami Miller School of Medicine, FL (United States)
  2. Univ. of California, Davis, CA (United States)
  3. 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.:
National Institutes of Health (NIH); American Heart Association; USDOE Office of Science (SC)
OSTI Identifier:
1432848
Grant/Contract Number:  
AC02-06CH11357; NIH-HL123255; NIH-HL096819; NIH-NIGMS 9P41-GM103622; 15PRE23020006; 17PRE33650085; 15POST25080302
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
Proceedings of the National Academy of Sciences of the United States of America
Additional Journal Information:
Journal Volume: 115; Journal Issue: 10; Journal ID: ISSN 0027-8424
Publisher:
National Academy of Sciences
Country of Publication:
United States
Language:
ENGLISH
Subject:
60 APPLIED LIFE SCIENCES; MYL2; myosin RLC; DCM; transgenic D94A mice; invasive hemodynamics

Citation Formats

Yuan, Chen-Ching, Kazmierczak, Katarzyna, Liang, Jingsheng, Zhou, Zhiqun, Yadav, Sunil, Gomes, Aldrin V., Irving, Thomas C., and Szczesna-Cordary, Danuta. Sarcomeric perturbations of myosin motors lead to dilated cardiomyopathy in genetically modified MYL2 mice. United States: N. p., 2018. Web. doi:10.1073/pnas.1716925115.
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Yuan, Chen-Ching, Kazmierczak, Katarzyna, Liang, Jingsheng, Zhou, Zhiqun, Yadav, Sunil, Gomes, Aldrin V., Irving, Thomas C., & Szczesna-Cordary, Danuta. Sarcomeric perturbations of myosin motors lead to dilated cardiomyopathy in genetically modified MYL2 mice. United States. https://doi.org/10.1073/pnas.1716925115
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Yuan, Chen-Ching, Kazmierczak, Katarzyna, Liang, Jingsheng, Zhou, Zhiqun, Yadav, Sunil, Gomes, Aldrin V., Irving, Thomas C., and Szczesna-Cordary, Danuta. Tue . "Sarcomeric perturbations of myosin motors lead to dilated cardiomyopathy in genetically modified MYL2 mice". United States. https://doi.org/10.1073/pnas.1716925115. https://www.osti.gov/servlets/purl/1432848.
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@article{osti_1432848,
title = {Sarcomeric perturbations of myosin motors lead to dilated cardiomyopathy in genetically modified MYL2 mice},
author = {Yuan, Chen-Ching and Kazmierczak, Katarzyna and Liang, Jingsheng and Zhou, Zhiqun and Yadav, Sunil and Gomes, Aldrin V. and Irving, Thomas C. and Szczesna-Cordary, Danuta},
abstractNote = {Dilated cardiomyopathy (DCM) is a devastating heart disease that affects about 1 million people in the United States, but the underlying mechanisms remain poorly understood. In this study, we aimed to determine the biomechanical and structural causes of DCM in transgenic mice carrying a novel mutation in theMYL2gene, encoding the cardiac myosin regulatory light chain. Transgenic D94A (aspartic acid-to-alanine) mice were created and investigated by echocardiography and invasive hemodynamic and molecular structural and functional assessments. Consistent with the DCM phenotype, a significant reduction of the ejection fraction (EF) was observed in ~5- and ~12-mo-old male and female D94A lines compared with respective WT controls. Younger male D94A mice showed a more pronounced left ventricular (LV) chamber dilation compared with female counterparts, but both sexes of D94A lines developed DCM by 12 mo of age. The hypocontractile activity of D94A myosin motors resulted in the rightward shift of the force–pCa dependence and decreased actin-activated myosin ATPase activity. Consistent with a decreased Ca2+sensitivity of contractile force, a small-angle X-ray diffraction study, performed in D94A fibers at submaximal Ca2+concentrations, revealed repositioning of the D94A cross-bridge mass toward the thick-filament backbone supporting the hypocontractile state of D94A myosin motors. Our data suggest that structural perturbations at the level of sarcomeres result in aberrant cardiomyocyte cytoarchitecture and lead to LV chamber dilation and decreased EF, manifesting in systolic dysfunction of D94A hearts. The D94A-induced development of DCM in mice closely follows the clinical phenotype and suggests thatMYL2may serve as a new therapeutic target for dilated cardiomyopathy.},
doi = {10.1073/pnas.1716925115},
url = {https://www.osti.gov/biblio/1432848}, journal = {Proceedings of the National Academy of Sciences of the United States of America},
issn = {0027-8424},
number = 10,
volume = 115,
place = {United States},
year = {2018},
month = {2}
}
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https://doi.org/10.1073/pnas.1716925115
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    Works referencing / citing this record:

    Therapeutic potential of AAV9-S15D-RLC gene delivery in humanized MYL2 mouse model of HCM
    journal, May 2019

    Hereditary heart disease: pathophysiology, clinical presentation, and animal models of HCM, RCM, and DCM associated with mutations in cardiac myosin light chains
    journal, January 2019

    Do Actomyosin Single-Molecule Mechanics Data Predict Mechanics of Contracting Muscle?
    journal, June 2018

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