Nadph Oxidase-Induced Oxidative Stress Impairs Autophagy in Dystrophic Skeletal Muscle

Duchenne muscular dystrophy (DMD) is a fatal degenerative muscle disease, attributed to a defect in the gene that encodes dystrophin. Emerging evidence implicates oxidative stress may impair autophagy in DMD patients and mdx mice, a model of DMD, by activating cytotoxic mediators. However, the specific source of ROS and the mechanism(s) of impaired autophagy have not yet been elucidated in dystrophic muscle. Therefore, understanding the interaction between oxidative stress and defects in autophagy is pivotal as we seek effective therapeutic targets in DMD. Here we demonstrated that nicotinamide adenine dinucleotide phosphatase (NADPH oxidase or Nox2)-induced oxidative stress was linked to impaired autophagy in mdx mice through Nox2-dependent superoxide production, Src kinase activation and further NOX2 activation via p47phox phosphorylation. The defect in autophagy was accompanied by persistent activation of Src kinase, which activated the autophagy repressor mammalian target of rapamycin (mTOR) via PI3K/Akt phosphorylation. Inhibition of Nox2 or Src kinase reduced oxidative stress and partially rescued the defective autophagy in mdx mice. We also have genetically down-regulated Nox2 activity in the mdx mouse to further corroborate that NADPH oxidase was the main source of oxidative stress, which impaired autophagy in DMD. Our data highlights novel pathogenic aspects of DMD and proposes NADPH oxidase as a potential therapeutic target.