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 Conflict of interest: none declared * Co-author Approval StatementThe manuscript, or part of it, has neither been published nor is currently under consideration for publication by any other journal. The co-authors have read the manuscript and approved this submission. Authors have no conflict of interests. * Conflict of Interest StatementThe manuscript, or part of it, has neither been published nor is currently under consideration for publication by any other journal. The co-authors have read the manuscript and approved this submission. Authors have no conflict of interests.Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. HHS Public Access Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript 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. Graphical Abstract KeywordsDystrophic cardiomyopathy; sodium overload; mitochondria; metabolism; oxidative stress

Alterations in Low-Z Elements Distribution in Heart Tissue after Treatments to Breast Cancer Using LEXRF Technique

“…These organelles generate ATP from metabolites through oxidative phosphorylation. Degradation in mitochondrial structure was correlated with substantial and persistent elevation in resting cytosolic sodium levels [33]. The LEXRF images show that sodium is more concentrated in the nucleus of the cardiomyocytes.…”

Cardio-protective effects of cyclosporine in doxorubicin induced cardiotoxicity and assessment of Interleukin-17 as biomarker of cardiac injury an animal model study

“…Countless, studies showed the cardioprotective role of cyclosporine on the heart in different situation in coronary artery bypass graft (GABG) and ischemic-reperfusion injury(IRI [26].In the cardiac injury that occurred as a result of ischemia and myocardial infarction the mitochondria play an important role in the cardiac cell homeostasis and any mitochondrial dysfunction that occurred through opening of the mitochondrial permeability transition pore which considered as critical determinant of cardiomyocyte death in the heart [27].In addition, the use of cyclosporine to prevent mitochondrial permeability transition pore opening at the onset of reperfusion will limiting myocardial infarction size [28].Additionally, cardiotoxicity induced by doxorubicin lead to free radical production which will coalesce with membrane phospholipids and cause lipid peroxidation thus, increase in the MDA level causing cell damage and necrosis [29]. The mitochondrial dysfunction due to fatty acid oxidation may increase the ischemic damage which leads to cell depletion from high-energy phosphate due to mitochondrial enzyme dysfunction and subsequently the mitochondrial membrane was depolarized and mitochondrial membrane transition pores will be opened and the mitochondrial reactive oxygen species will increase and exacerbates the oxidative stress [30].Thus, the utilizing of cyclosporine will protects the heart from oxidative stress and will restoring the pore to the original state which has protective effect to cardiomyocyte.…”

Duchenne Muscular Dystrophy: Emerging Pathological Role for Cardiac Myopathy

“…Overview Ventricular cardiomyocytes isolated from hearts of a mouse model of DMD (mdx mice) exhibit a number of distinct characteristics compared to cells from hearts of wild type (control group) animals: 1) their plasmalemmal membrane is more fragile [10,11]; 2) ionic fluxes across the membrane are increased [11,15]; 3) resting cytosolic Ca 2+ and Na + levels are elevated [11,15,16]; 4) intracellular Ca 2+ transients evoked by mechanical challenges are enhanced [10,17,18]; 5) excitation-contraction coupling (EC-coupling) is hypersensitive [19,20]; 6) the cytosolic compartment is severely oxidized due to enhanced activity of sarcolemmal NAD(P)H oxidase type II (NOX2) [16,21]; 7) mitochondrial redox state is shifted towards a more oxidative state [22]; and 8) mitochondria undergo irreversible depolarizations during increased workload due to enhanced opening of mitochondrial permeability transitions pore [16,22,23]. Moreover, damaged mitochondria are not efficiently removed from the hearts due to deficiency in the PINK1/PARKIN mitophagy pathway [24], eventually leading to the deficit in ATP supply.…”

“…This results in reverse operation of ATP-synthase to the point where it consumes ATP instead of producing it. This, in turn, facilitates cell death by apoptotic or necrotic mechanisms [22]. To make things worse, impaired mitochondrial autophagy has been recently demonstrated in DMD [24].…”