296 - Reversal of age related post-translational modifications improves mitochondrial and skeletal muscle function through redox dependent mechanisms

Abstract

Muscle redox status and post-translational modifications (PTMs) regulate diverse aspects of skeletal muscle function, including mitochondrial energetics and contractile performance. In aging skeletal muscle mitochondrial oxidative stress contributes to altered redox homeostasis. We have previously demonstrated that reducing mitochondrial oxidant production with acute (1 hr) and chronic (8 week) treatment with the peptide elamipretide (SS-31) can reverse skeletal muscle and mitochondrial dysfunction and reduce redox stress in aging mice. These improvements were also associated with increased exercise tolerance and greater fatigue resistance. However, the mechanisms by which improving mitochondrial function with SS-31 reverses age-related decline in skeletal muscle function remain unknown. To investigate the effect of SS-31 on the skeletal muscle proteome we assessed global changes in protein abundance, and phosphorylation and S-glutathionylation PTMs in young vs. aged and aged+SS-31 vs. aged mice. Osmotically regulated pumps were surgically implanted into 26-month old female C57Bl/6 mice to deliver saline or SS-31 (3mg/kg/day) for 8 weeks. At the end of 8-week treatment, animals were dissected and gastrocnemius muscle was separated and flash-frozen for analysis via mass spectrometry. Seven-month old female C57Bl/mice were sacrificed as healthy young controls. Relatively few significant protein abundance changes occur with age in skeletal muscle (43) using a false discovery rate of