High glucose-induced oxidative stress accelerates myogenesis by altering SUMO reactions

Skeletal muscle preservation is a dynamic process that involves constant repair and regeneration. However, the regenerative capacity of muscle cells declines in hyperglycemia. This study aimed to explore the molecular mechanisms underlying this glucotoxicity during myoblast differentiation. C2C12 cells were exposed to different concentrations of glucose, to recapitulate the development of skeletal muscles in vivo in normo- and hyperglycemic conditions. In high glucose conditions, we found significant increases in levels of total cellular reactive oxygen species (ROS) and a reorganization of SUMO enzyme transcripts and SUMOylated proteins. Furthermore, in anticipation of the ROS-induced damage to newly formed myotubes, we observed acceleration of myogenesis. Interestingly, we found a tight relationship between SUMOylation of the Histone methyltransferase SET7/9 and the maintenance of sarcomeric structures of newly formed myotubes. Finally, treatment with the antioxidant anacardic acid preserved the function and activity of myotubes generated in high-glucose conditions by interfering with both ROS and SUMO pathways. Combined, these results suggest that increased oxidative stress and modulation of SUMO reactions are key mediators of glucotoxicity and inhibition of these perturbations using antioxidants might improve muscle regeneration in hyperglycemia.