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

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Authors: Ait Mou, Y; Lacampagne, A.; Irving, T; Scheuermann, V.; Blot, S.; Ghaleh, B.; de Tombe, P. P.; Cazorla, O
Article 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 (1.9mum). 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#39; 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.
Journal Title: Journal of Molecular and Cellular Cardiology
Volume: 114
ISSN: 1095-8584; 0022-2828
Publisher: Unknown  
Journal Place: England
Date Published: 2018
Start Page: 345
End Page: 353
Language: eng
DOI/URL:

S0022-2828(17)30364-4
Notes: LR: 20180320; CI: Copyright (c) 2017; GR: P01 HL062426/HL/NHLBI NIH HHS/United States; GR: P41 GM103622/GM/NIGMS NIH HHS/United States; JID: 0262322; NIHMS931956; OTO: NOTNLM; PMCR: 2019/01/01 00:00; 2017/07/24 00:00 [received]; 2017/11/28 00:00 [revised]; 2017/12/20 00:00 [accepted]; 2019/01/01 00:00 [pmc-release]; 2017/12/25 06:00 [pubmed]; 2017/12/25 06:00 [medline]; 2017/12/25 06:00 [entrez]; ppublish