Superoxide-mediated oxidative stress accelerates skeletal muscle atrophy by synchronous activation of proteolytic systems

Young C. Jang, Karl Rodriguez, Michael S. Lustgarten, Florian L. Muller, Arunabh Bhattacharya, Anson Pierce, Jeongmoon J. Choi, Nan Hee Lee, Asish Chaudhuri, Arlan G Richardson, Holly Vanremmen

Research output: Contribution to journalArticle

Abstract

The maintenance of skeletal muscle mass depends on the overall balance between the rates of protein synthesis and degradation. Thus, age-related muscle atrophy and function, commonly known as sarcopenia, may result from decreased protein synthesis, increased proteolysis, or simultaneous changes in both processes governed by complex multifactorial mechanisms. Growing evidence implicates oxidative stress and reactive oxygen species (ROS) as an essential regulator of proteolysis. Our previous studies have shown that genetic deletion of CuZn superoxide dismutase (CuZnSOD, Sod1) in mice leads to elevated oxidative stress, muscle atrophy and weakness, and an acceleration in age-related phenotypes associated with sarcopenia. The goal of this study is to determine whether oxidative stress directly influences the acceleration of proteolysis in skeletal muscle of Sod1−/− mice as a function of age. Compared to control, Sod1−/− muscle showed a significant elevation in protein carbonyls and 3-nitrotyrosine levels, suggesting high oxidative and nitrosative protein modifications were present. In addition, age-dependent muscle atrophy in Sod1−/− muscle was accompanied by an upregulation of the cysteine proteases, calpain, and caspase-3, which are known to play a key role in the initial breakdown of sarcomeres during atrophic conditions. Furthermore, an increase in oxidative stress-induced muscle atrophy was also strongly coupled with simultaneous activation of two major proteolytic systems, the ubiquitin-proteasome and lysosomal autophagy pathways. Collectively, our data suggest that chronic oxidative stress in Sod1−/− mice accelerates age-dependent muscle atrophy by enhancing coordinated activation of the proteolytic systems, thereby resulting in overall protein degradation.

Original languageEnglish (US)
JournalGeroScience
DOIs
StateAccepted/In press - Jan 1 2020

Keywords

  • Autophagy
  • Muscle atrophy
  • Protein oxidation
  • Proteolysis
  • Sarcopenia
  • Ubiquitin proteasome

ASJC Scopus subject areas

  • Aging
  • Geriatrics and Gerontology

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    Jang, Y. C., Rodriguez, K., Lustgarten, M. S., Muller, F. L., Bhattacharya, A., Pierce, A., Choi, J. J., Lee, N. H., Chaudhuri, A., Richardson, A. G., & Vanremmen, H. (Accepted/In press). Superoxide-mediated oxidative stress accelerates skeletal muscle atrophy by synchronous activation of proteolytic systems. GeroScience. https://doi.org/10.1007/s11357-020-00200-5