Src-dependent impairment of autophagy by oxidative stress in a mouse model of Duchenne muscular dystrophy

Rituraj Pal, Michela Palmieri, James A. Loehr, Shumin Li, Reem Abo-Zahrah, Tanner O. Monroe, Poulami B. Thakur, Marco Sardiello and George G. Rodney ()
Additional contact information
Rituraj Pal: Baylor College of Medicine
Michela Palmieri: Human Genetics, Baylor College of Medicine
James A. Loehr: Baylor College of Medicine
Shumin Li: Baylor College of Medicine
Reem Abo-Zahrah: Baylor College of Medicine
Tanner O. Monroe: Baylor College of Medicine
Poulami B. Thakur: Baylor College of Medicine
Marco Sardiello: Human Genetics, Baylor College of Medicine
George G. Rodney: Baylor College of Medicine

Nature Communications, 2014, vol. 5, issue 1, 1-10

Abstract: Abstract Duchenne muscular dystrophy (DMD) is a fatal degenerative muscle disease resulting from mutations in the dystrophin gene. Increased oxidative stress and altered Ca2+ 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.

Date: 2014
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/ncomms5425 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms5425

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/ncomms5425

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().