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Title: Altered myofilament structure and function in dogs with Duchenne muscular dystrophy cardiomyopathy

Abstract

Aim Duchenne Muscular Dystrophy (DMD) is associated with progressive depressed left ventricular (LV) function. However, DMD effects on myofilament structure and function are poorly understood. Golden Retriever Muscular Dystrophy (GRMD) is a dog model of DMD recapitulating the human form of DMD. Objective The objective of this study is to evaluate myofilament structure and function alterations in GRMD model with spontaneous cardiac failure. Methods and results We have employed synchrotron X-rays diffraction to evaluate myofilament lattice spacing at various sarcomere lengths (SL) on permeabilized LV myocardium. We found a negative correlation between SL and lattice spacing in both sub-epicardium (EPI) and sub-endocardium (ENDO) LV layers in control dog hearts. In the ENDO of GRMD hearts this correlation is steeper due to higher lattice spacing at short SL (1.9 μm). Furthermore, cross-bridge cycling indexed by the kinetics of tension redevelopment (ktr) was faster in ENDO GRMD myofilaments at short SL. We measured post-translational modifications of key regulatory contractile proteins. S-glutathionylation of cardiac Myosin Binding Protein-C (cMyBP-C) was unchanged and PKA dependent phosphorylation of the cMyBP-C was significantly reduced in GRMD ENDO tissue and more modestly in EPI tissue. Conclusions We found a gradient of contractility in control dogs' myocardium that spreadsmore » across the LV wall, negatively correlated with myofilament lattice spacing. Chronic stress induced by dystrophin deficiency leads to heart failure that is tightly associated with regional structural changes indexed by increased myofilament lattice spacing, reduced phosphorylation of regulatory proteins and altered myofilament contractile properties in GRMD dogs.« less

Authors:
ORCiD logo; ; ; ; ; ; ;
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
National Institutes of Health (NIH)
OSTI Identifier:
1418033
Resource Type:
Journal Article
Journal Name:
Journal of Molecular and Cellular Cardiology
Additional Journal Information:
Journal Volume: 114; Journal Issue: C; Journal ID: ISSN 0022-2828
Publisher:
Elsevier
Country of Publication:
United States
Language:
ENGLISH
Subject:
60 APPLIED LIFE SCIENCES

Citation Formats

Ait Mou, Younss, Lacampagne, Alain, Irving, Thomas, Scheuermann, Valérie, Blot, Stéphane, Ghaleh, Bijan, de Tombe, Pieter P., and Cazorla, Olivier. Altered myofilament structure and function in dogs with Duchenne muscular dystrophy cardiomyopathy. United States: N. p., 2018. Web. doi:10.1016/j.yjmcc.2017.12.008.
Ait Mou, Younss, Lacampagne, Alain, Irving, Thomas, Scheuermann, Valérie, Blot, Stéphane, Ghaleh, Bijan, de Tombe, Pieter P., & Cazorla, Olivier. Altered myofilament structure and function in dogs with Duchenne muscular dystrophy cardiomyopathy. United States. doi:10.1016/j.yjmcc.2017.12.008.
Ait Mou, Younss, Lacampagne, Alain, Irving, Thomas, Scheuermann, Valérie, Blot, Stéphane, Ghaleh, Bijan, de Tombe, Pieter P., and Cazorla, Olivier. Mon . "Altered myofilament structure and function in dogs with Duchenne muscular dystrophy cardiomyopathy". United States. doi:10.1016/j.yjmcc.2017.12.008.
@article{osti_1418033,
title = {Altered myofilament structure and function in dogs with Duchenne muscular dystrophy cardiomyopathy},
author = {Ait Mou, Younss and Lacampagne, Alain and Irving, Thomas and Scheuermann, Valérie and Blot, Stéphane and Ghaleh, Bijan and de Tombe, Pieter P. and Cazorla, Olivier},
abstractNote = {Aim Duchenne Muscular Dystrophy (DMD) is associated with progressive depressed left ventricular (LV) function. However, DMD effects on myofilament structure and function are poorly understood. Golden Retriever Muscular Dystrophy (GRMD) is a dog model of DMD recapitulating the human form of DMD. Objective The objective of this study is to evaluate myofilament structure and function alterations in GRMD model with spontaneous cardiac failure. Methods and results We have employed synchrotron X-rays diffraction to evaluate myofilament lattice spacing at various sarcomere lengths (SL) on permeabilized LV myocardium. We found a negative correlation between SL and lattice spacing in both sub-epicardium (EPI) and sub-endocardium (ENDO) LV layers in control dog hearts. In the ENDO of GRMD hearts this correlation is steeper due to higher lattice spacing at short SL (1.9 μm). Furthermore, cross-bridge cycling indexed by the kinetics of tension redevelopment (ktr) was faster in ENDO GRMD myofilaments at short SL. We measured post-translational modifications of key regulatory contractile proteins. S-glutathionylation of cardiac Myosin Binding Protein-C (cMyBP-C) was unchanged and PKA dependent phosphorylation of the cMyBP-C was significantly reduced in GRMD ENDO tissue and more modestly in EPI tissue. Conclusions We found a gradient of contractility in control dogs' myocardium that spreads across the LV wall, negatively correlated with myofilament lattice spacing. Chronic stress induced by dystrophin deficiency leads to heart failure that is tightly associated with regional structural changes indexed by increased myofilament lattice spacing, reduced phosphorylation of regulatory proteins and altered myofilament contractile properties in GRMD dogs.},
doi = {10.1016/j.yjmcc.2017.12.008},
journal = {Journal of Molecular and Cellular Cardiology},
issn = {0022-2828},
number = C,
volume = 114,
place = {United States},
year = {2018},
month = {1}
}