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

By Younss Ait Mou, Alain Lacampagne, Thomas Irving, Valérie Scheuermann, Stéphane Blot, Bijan Ghaleh, Pieter de Tombe and Olivier Cazorla

Abstract

International audienceAim: 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

Topics: Contractile proteins, Heart failure, Hypertrophic cardiomyopathy, Left ventricular failure, Length dependent activation, myofilament properties, Muscular dystrophy, Transmural heterogeneity, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system
Publisher: Elsevier
Year: 2018
DOI identifier: 10.1016/j.yjmcc.2017.12.008
OAI identifier: oai:HAL:hal-02376879v1
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