Absence of CuZn superoxide dismuatase (SOD1) leads to increased proteolysis of skeletal muscle

Abstract

We recently reported a novel phenotype of age dependent muscle atrophy in the mice that are deficient in a major antioxidant enzyme CuZnSOD. To investigate the possible mechanism behind age depedent muscle loss in these mice, we examined the major proteolytic pathway in skeletal muscle of CuZnSOD knockout mice. Cysteine proteases, caspase-3 and calpain, have been shown to breakdown actomyosin complex and myofibrils during skeletal muscle atrophy. We found that caspase-3 activity was significantly increased in mice that are deficient in CuZnSOD. However, the activity of other Ca2+ dependent protease, calpain, did not reach the statistical significance. In addition, we observed age dependent increase in cytosolic ubiquitinated-proteins in CuZnSOD knockout mice. Furthermore, chymotrypsin-like 20S proteasome activity was also increased in these mice. Several investigators identified muscle specific E3 ligase, MuRF1 and MAFbx (Atrogin1), as a common ubiquitin ligase that increases their expression in different models of muscle atrophy. However, we did not detect any changes in protein levels of MuRF1 and MAFbx in CuZnSOD deficienct mice suggesting other muscle specific ligase might be involve in oxidative stress induced proteolysis via proteasome pathway.