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HHS Public AccessAuthor manuscriptNat Commun. Author manuscript; offered in PMC 2015 January 16.Published in final edited type as: Nat Commun. ; five: 4425. doi:ten.1038ncomms5425.Author Manuscript Author Manuscript Author Manuscript Author ManuscriptSrc-dependent impairment of autophagy by oxidative stress within a mouse model of Duchenne muscular dystrophyRituraj Pal1, Michela Palmieri2, James A. Loehr1, Shumin Li1, Reem Abo-Zahrah1, Tanner O. Monroe1, Poulami Basu Thakur1, Marco Sardiello2, and George G. Rodney1,1Departmentof Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX of Molecular Human Genetics, Baylor College of Medicine, Houston, TX U.S.AU.S.A2DepartmentAbstractDuchenne muscular dystrophy (DMD) is actually a fatal degenerative muscle illness resulting from mutations within the dystrophin gene. Increased oxidative strain and altered Ca2 homeostasis are hallmarks of dystrophic muscle. Though impaired autophagy has recently been implicated inside the illness procedure, the mechanisms underlying the impairment have not been elucidated. Right here we show that nicotinamide adenine dinucleotide phosphatase (Nox2)-induced oxidative stress impairs each autophagy and lysosome formation in mdx mice. Persistent activation of Src kinase results in activation of the autophagy repressor Aurora A MedChemExpress mammalian target of rapamycin (mTOR) through PI3KAkt phosphorylation. Inhibition of Nox2 or Src kinase reduces oxidative anxiety and partially rescues the defective autophagy and lysosome biogenesis. Genetic down regulation of Nox2 activity in the mdx mouse decreases ROS production, abrogates defective autophagy and rescues histological abnormalities and contractile impairment. Our information highlight mechanisms underlying the pathogenesis of DMD and identify NADPH oxidase and Src kinase as prospective therapeutic targets. Duchenne muscular dystrophy (DMD) could be the most common X-linked lethal disorder in humans. It can be caused by mutations inside the dystrophin gene 1, 2, resulting in progressive skeletal muscle degeneration and ultimately top to paralysis and death 3. Even though there’s intense study focused on gene and cell primarily based therapy, to date there is absolutely no cure for DMD. Pharmacological primarily based remedies are aimed at controlling the progression of symptoms, acquiring time till a genetic or cell primarily based therapy is realized. How dysfunctional pathways within the dystrophic muscle lead to degeneration is still a matter of intense investigation. The characterization on the culprit pathway(s) linking mutations in dystrophin to muscleUsers may well view, print, copy, and download text and data-mine the content material in such documents, for the purposes of academic research, subject usually to the full Situations of use:http:natureauthorseditorial_policieslicense.html#terms All correspondence need to be sent to rodneybcm.edu.. Author contributions R.P. and G.G.R. conceived and designed the experiments. R.P., M.P., J.A.L., S.L., R.A., and T.O.M. performed the experim.
