title: Mitochondrial dysfunctions during progression of dystrophic cardiomyopathy.
abstract: Duchenne muscular dystrophy (DMD) is a progressive muscle disease with severe cardiac complications. It is believed that cellular oxidative stress and augmented Ca(2+) signaling drives the development of cardiac pathology. Some mitochondrial and metabolic dysfunctions have also been reported. Here we investigate cellular mechanisms responsible for impaired mitochondrial metabolism in dystrophic cardiomyopathy at early stages of the disease. We employed electrophysiological and imaging techniques to study mitochondrial structure and function in cardiomyocytes from mdx mice, an animal model of DMD. Here we show that mitochondrial matrix was progressively oxidized in myocytes isolated from mdx mice. Moreover, an abrupt increase in workload resulted in significantly more pronounced oxidation of mitochondria in dystrophic cells. Electron micrographs revealed a gradually increased number of damaged mitochondria in mdx myocytes. Degradation in mitochondrial structure was correlated with progressive increase in mitochondrial Ca(2+) sequestration and mitochondrial depolarization, despite a substantial and persistent elevation in resting cytosolic sodium levels. Treatment of mdx cells with cyclosporine A, an inhibitor of mitochondrial permeability transition pore (mPTP), shifted both resting and workload-dependent mitochondrial redox state to the levels recorded in control myocytes. It also significantly reduced workload dependent depolarization of mitochondrial membrane in dystrophic cardiomyocytes. Overall, our studies highlight age dependent deterioration of mitochondrial function in dystrophic cardiomyocytes, which seems to be associated with excessive opening of mPTP due to oxidative stress and cellular Ca(2+) overload.
authors.affiliation: Department of Pharmacology and Physiology, New Jersey Medical School - Rutgers University, Newark 07103, NJ, USA.
authors.forename: Victoria
authors.initials: V
authors.lastname: Kyrychenko
authors.affiliation: Department of Pharmacology and Physiology, New Jersey Medical School - Rutgers University, Newark 07103, NJ, USA.
authors.forename: Eva
authors.initials: E
authors.lastname: Poláková
authors.affiliation: Department of Pharmacology and Physiology, New Jersey Medical School - Rutgers University, Newark 07103, NJ, USA.
authors.forename: Radoslav
authors.initials: R
authors.lastname: Janíček
authors.affiliation: Department of Pharmacology and Physiology, New Jersey Medical School - Rutgers University, Newark 07103, NJ, USA. Electronic address: nshiroko@njms.rutgers.edu.
authors.forename: Natalia
authors.initials: N
authors.lastname: Shirokova
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D016572:Cyclosporine / Q000494:pharmacology; D003600:Cytosol / Q000378:metabolism; D004195:Disease Models, Animal; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018101:Mice, Inbred mdx; D008929:Mitochondria, Heart / Q000378:metabolism* / Q000648:ultrastructure; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D020388:Muscular Dystrophy, Duchenne / Q000378:metabolism / Q000473:pathology*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009243:NAD / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D012964:Sodium / Q000378:metabolism
chemical_list: D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D009243:NAD; D016572:Cyclosporine; D012964:Sodium; D002118:Calcium
keywords: Dystrophic cardiomyopathy; Metabolism; Mitochondria; Oxidative stress; Sodium overload