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      Defects in Mitochondrial ATP Synthesis in Dystrophin-Deficient Mdx Skeletal Muscles May Be Caused by Complex I Insufficiency

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          Abstract

          Duchenne Muscular Dystrophy is a chronic, progressive and ultimately fatal skeletal muscle wasting disease characterised by sarcolemmal fragility and intracellular Ca 2+ dysregulation secondary to the absence of dystrophin. Mounting literature also suggests that the dysfunction of key energy systems within the muscle may contribute to pathological muscle wasting by reducing ATP availability to Ca 2+ regulation and fibre regeneration. No study to date has biochemically quantified and contrasted mitochondrial ATP production capacity by dystrophic mitochondria isolated from their pathophysiological environment such to determine whether mitochondria are indeed capable of meeting this heightened cellular ATP demand, or examined the effects of an increasing extramitochondrial Ca 2+ environment. Using isolated mitochondria from the diaphragm and tibialis anterior of 12 week-old dystrophin-deficient mdx and healthy control mice (C57BL10/ScSn) we have demonstrated severely depressed Complex I-mediated mitochondrial ATP production rate in mdx mitochondria that occurs irrespective of the macronutrient-derivative substrate combination fed into the Kreb’s cycle, and, which is partially, but significantly, ameliorated by inhibition of Complex I with rotenone and stimulation of Complex II-mediated ATP-production with succinate. There was no difference in the MAPR response of mdx mitochondria to increasing extramitochondrial Ca 2+ load in comparison to controls, and 400 nM extramitochondrial Ca 2+ was generally shown to be inhibitory to MAPR in both groups. Our data suggests that DMD pathology is exacerbated by a Complex I deficiency, which may contribute in part to the severe reductions in ATP production previously observed in dystrophic skeletal muscle.

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          Most cited references35

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          Survival in Duchenne muscular dystrophy: improvements in life expectancy since 1967 and the impact of home nocturnal ventilation.

          We reviewed the notes of 197 patients with Duchenne muscular dystrophy whose treatment was managed at the Newcastle muscle centre from 1967 to 2002, to determine whether survival has improved over the decades and whether the impact of nocturnal ventilation altered the pattern of survival. Patients were grouped according to the decade of death and whether or not they were ventilated. Kaplan Meier survival analyses showed significant decade on decade improvement in survival. Mean age of death in the 1960s was 14.4 years, whereas for those ventilated since 1990 it was 25.3 years. Cardiomyopathy significantly shortened life expectancy from 19 years to a mean age of 16.9 years. Better coordinated care probably improved the chances of survival to 25 years from 0% in the 1960s to 4% in the 1970s and 12% in the 1980s, but the impact of nocturnal ventilation has further improved this chance to 53% for those ventilated since 1990.
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            The mdx mouse diaphragm reproduces the degenerative changes of Duchenne muscular dystrophy.

            Although murine X-linked muscular dystrophy (mdx) and Duchenne muscular dystrophy (DMD) are genetically homologous and both characterized by a complete absence of dystrophin, the limb muscles of adult mdx mice suffer neither the detectable weakness nor the progressive degeneration that are features of DMD. Here we show that the mdx mouse diaphragm exhibits a pattern of degeneration, fibrosis and severe functional deficit comparable to that of DMD limb muscle, although adult mice show no overt respiratory impairment. Progressive functional changes include reductions in strength (to 13.5% of control by two years of age), elasticity, twitch speed and fibre length. The collagen density rises to at least seven times that of control diaphragm and ten times that of mdx hind-limb muscle. By 1.5 years of age, similar but less severe histological changes emerge in the accessory muscles of respiration. On the basis of these findings, we propose that dystrophin deficiency alters the threshold for work-induced injury. Our data provide a quantitative framework for studying the pathogenesis of dystrophy and extend the application of the mdx mouse as an animal model.
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              Bioenergetics and the formation of mitochondrial reactive oxygen species.

              The contribution of mitochondria to the manifestation of disease is ascribed largely to the production of reactive oxygen species (ROS), which are obligatory by-products of aerobiosis. Studies using isolated mitochondria have revealed multiple potential sites and circumstances of ROS production but the relevance of these to in situ conditions is limited. In this article, we focus on bioenergetic factors that promote ROS generation at physiologically relevant sites in mitochondria. Emphasis is given to ROS generation by complex I--the first component of the respiratory chain--and to how the NADH:NAD+ ratio regulates ROS formation. Complex I is a physiologically and pathologically relevant ROS-forming site that is important not only in normal mitochondrial energy production but also in the pathogenesis of Parkinson's disease, which is the second most common neurodegenerative disease.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2014
                26 December 2014
                : 9
                : 12
                : e115763
                Affiliations
                [1 ]Centre for Chronic Disease Prevention and Management, College of Health and Biomedicine, Victoria University, Melbourne, Victoria, Australia
                [2 ]Institute of Sport, Exercise & Active Living (ISEAL), Victoria University, Melbourne, Victoria, Australia
                [3 ]Australian Institute of Musculoskeletal Science, Western Health, Victoria, Australia
                [4 ]School of Human Life Sciences, University of Tasmania, Launceston, Australia
                University of Minnesota, United States of America
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: ER MC AW AH. Performed the experiments: ER CT AW. Analyzed the data: ER CT MC AW AH. Contributed reagents/materials/analysis tools: ER AW AH. Contributed to the writing of the manuscript: ER CT MC AW AH.

                Article
                PONE-D-14-34270
                10.1371/journal.pone.0115763
                4277356
                25541951
                08c12644-027e-4d4d-a9ce-9b564b67546c
                Copyright @ 2014

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 30 July 2014
                : 1 December 2014
                Page count
                Pages: 16
                Funding
                The authors have no support or funding to report.
                Categories
                Research Article
                Biology and Life Sciences
                Anatomy
                Musculoskeletal System
                Muscles
                Muscle Fibers
                Skeletal Muscle Fibers
                Muscle Components
                Biochemistry
                Bioenergetics
                Electron Transport Chain
                Energy-Producing Organelles
                Metabolism
                Energy Metabolism
                Metabolic Pathways
                Genetics
                Heredity
                Genetic Linkage
                Sex Linkage
                X-Linked Traits
                Duchenne Muscular Dystrophy
                Physiology
                Muscle Physiology
                Muscle Biochemistry
                Physiological Processes
                Medicine and Health Sciences
                Clinical Genetics
                Mitochondrial Diseases
                Mitochondrial Myopathy
                Genetic Diseases
                Custom metadata
                The authors confirm that all data underlying the findings are fully available without restriction. All relevant data are within the paper and its supporting information files.

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