skip to main content
OSTI.GOV title logo U.S. Department of Energy
Office of Scientific and Technical Information

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]
  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.
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
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.
@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}
}

Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record

Citation Metrics:
Cited by: 7 works
Citation information provided by
Web of Science

Save / Share:

Works referenced in this record:

Calreticulin signals upstream of calcineurin and MEF2C in a critical Ca 2+ -dependent signaling cascade
journal, July 2005


Stretching the lever-arm theory
journal, January 2002


Prolonged Ca2+ and Force Transients in Myosin RLC Transgenic Mouse Fibers Expressing Malignant and Benign FHC Mutations
journal, August 2006


The Filament Lattice of Striated Muscle
journal, April 1998


Mechanistic Pathways of Sex Differences in Cardiovascular Disease
journal, January 2017


Cardiac Myosin Activation: A Potential Therapeutic Approach for Systolic Heart Failure
journal, March 2011


A Model for Random Sampling and Estimation of Relative Protein Abundance in Shotgun Proteomics
journal, July 2004


Constitutive phosphorylation of cardiac myosin regulatory light chain prevents development of hypertrophic cardiomyopathy in mice
journal, June 2015


Dilated cardiomyopathy in homozygous myosin-binding protein-C mutant mice
journal, November 1999


Dilated cardiomyopathy: the complexity of a diverse genetic architecture
journal, July 2013


Dilated Cardiomyopathy A Disease of the Intercalated Disc?
journal, January 2003


Ventricular–Vascular Interaction in Heart Failure
journal, January 2008


Cardiac inflammation in genetic dilated cardiomyopathy caused by MYBPC3 mutation
journal, January 2017


A Tension-Based Model Distinguishes Hypertrophic versus Dilated Cardiomyopathy
journal, May 2016


Myosin Regulatory Light Chain (RLC) Phosphorylation Change as a Modulator of Cardiac Muscle Contraction in Disease
journal, March 2013


Novel familial dilated cardiomyopathy mutation in MYL2 affects the structure and function of myosin regulatory light chain
journal, April 2015


Cardiac myosin missense mutations cause dilated cardiomyopathy in mouse models and depress molecular motor function
journal, September 2006


Experimental models of inherited cardiomyopathy and its therapeutics
journal, January 2014


Regulatory Light Chains of Striated Muscle Myosin. Structure, Function and Malfunction
journal, June 2003


α-Myosin Heavy Chain: A Sarcomeric Gene Associated With Dilated and Hypertrophic Phenotypes of Cardiomyopathy
journal, July 2005


The effect of myosin light chain 2 dephosphorylation on Ca-sensitivity of force is enhanced in failing human hearts
journal, February 2003


Personalizing Risk Stratification for Sudden Death in Dilated Cardiomyopathy: The Past, Present, and Future
journal, July 2017


Ventriculo-arterial decoupling in acutely altered hemodynamic states
journal, January 2013


Animal Models of Heart Failure: A Scientific Statement From the American Heart Association
journal, June 2012


European Cardiomyopathy Pilot Registry: EURObservational Research Programme of the European Society of Cardiology
journal, September 2015


Mouse and computational models link Mlc2v dephosphorylation to altered myosin kinetics in early cardiac disease
journal, April 2012


Knock-In Mouse Model of Dilated Cardiomyopathy Caused by Troponin Mutation
journal, July 2007


    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