title: Src-dependent impairment of autophagy by oxidative stress in a mouse model of Duchenne muscular dystrophy.
abstract: Duchenne muscular dystrophy (DMD) is a fatal degenerative muscle disease resulting from mutations in the dystrophin gene. Increased oxidative stress and altered Ca(2+) homeostasis are hallmarks of dystrophic muscle. While impaired autophagy has recently been implicated in the disease process, the mechanisms underlying the impairment have not been elucidated. Here we show that nicotinamide adenine dinucleotide phosphatase (Nox2)-induced oxidative stress impairs both autophagy and lysosome formation in mdx mice. Persistent activation of Src kinase leads to activation of the autophagy repressor mammalian target of rapamycin (mTOR) via PI3K/Akt phosphorylation. Inhibition of Nox2 or Src kinase reduces oxidative stress and partially rescues the defective autophagy and lysosome biogenesis. Genetic downregulation of Nox2 activity in the mdx mouse decreases reactive oxygen species (ROS) production, abrogates defective autophagy and rescues histological abnormalities and contractile impairment. Our data highlight mechanisms underlying the pathogenesis of DMD and identify NADPH oxidase and Src kinase as potential therapeutic targets.
authors.affiliation: Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Rituraj
authors.initials: R
authors.lastname: Pal
authors.affiliation: Department of Molecular, Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Michela
authors.initials: M
authors.lastname: Palmieri
authors.affiliation: Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: James A
authors.initials: JA
authors.lastname: Loehr
authors.affiliation: Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Shumin
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Reem
authors.initials: R
authors.lastname: Abo-Zahrah
authors.affiliation: Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Tanner O
authors.initials: TO
authors.lastname: Monroe
authors.affiliation: Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Poulami B
authors.initials: PB
authors.lastname: Thakur
authors.affiliation: Department of Molecular, Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Marco
authors.initials: M
authors.lastname: Sardiello
authors.affiliation: Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: George G
authors.initials: GG
authors.lastname: Rodney
mesh_terms: D000818:Animals; D001343:Autophagy / Q000235:genetics / Q000502:physiology*; D004195:Disease Models, Animal; D047468:Immunoprecipitation; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009137:Muscular Dystrophy, Animal / Q000378:metabolism* / Q000473:pathology; D020388:Muscular Dystrophy, Duchenne / Q000378:metabolism*; D018384:Oxidative Stress / Q000235:genetics / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D017382:Reactive Oxygen Species