Younss Ait Mou1, Alain Lacampagne2, Thomas Irving3, Valérie Scheuermann2, Stéphane Blot4, Bijan Ghaleh5, Pieter P de Tombe6, Olivier Cazorla7. 1. College of Science and Engineering, Hamad Bin Khalifa University, Doha, Qatar; Department of Cell and Molecular Physiology, Heath Science Division, Loyola University Chicago, Maywood, IL 60153, USA. 2. INSERM U1046, CNRS UMR 9214, Université de Montpellier, Physiologie et Médecine Expérimentale du cœur et des muscles - PHYMEDEXP, CHU Arnaud de Villeneuve, 34295 Montpellier cedex 05, France. 3. Department of Cell and Molecular Physiology, Heath Science Division, Loyola University Chicago, Maywood, IL 60153, USA; Department of Biological Sciences, Illinois Institute of Technology, Chicago, IL 60616, USA. 4. Inserm U955-E10, IMRB, Université Paris Est, Ecole nationale vétérinaire d'Alfort, Maisons-Alfort 94700, France. 5. INSERM U 955, Créteil, France. 6. Department of Cell and Molecular Physiology, Heath Science Division, Loyola University Chicago, Maywood, IL 60153, USA. 7. INSERM U1046, CNRS UMR 9214, Université de Montpellier, Physiologie et Médecine Expérimentale du cœur et des muscles - PHYMEDEXP, CHU Arnaud de Villeneuve, 34295 Montpellier cedex 05, France.. Electronic address: olivier.cazorla@inserm.fr.
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 (1.9μm). 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.
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 (1.9μm). 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.
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