Superoxide is an Intrinsic Signaling Molecule Triggering Muscle Hypertrophy

Aims: Redox signaling plays a key role in skeletal muscle remodeling induced by exercise and prolonged inactivity, but it is unclear which oxidant triggers myofiber hypertrophy due to the lack of strategies to precisely regulate individual oxidants in vivo. In this study, we used tetrathiomolybdate (TM) to dissociate the link between superoxide (O₂^•-) and hydrogen peroxide and thereby to specifically explore the role of O₂^•- in muscle hypertrophy in C2C12 cells and mice. Results: TM can linearly regulate intracellular O₂^•- levels by inhibition of superoxide dismutase 1 (SOD1). A 70% increase in O₂^•- levels in C2C12 myoblast cells and mice is necessary and sufficient for triggering hypertrophy of differentiated myotubes and can enhance exercise performance by more than 50% in mice. SOD1 knockout blocks TM-induced O₂^•- increments and thereby prevents hypertrophy, whereas SOD1 restoration rescues all these effects. Scavenging O₂^•- with antioxidants abolishes TM-induced hypertrophy and the enhancement of exercise performance, whereas the restoration of O₂^•- levels with a O₂^•- generator promotes muscle hypertrophy independent of SOD1 activity. Innovation and Conclusion: These findings suggest that O₂^•- is an endogenous initiator of myofiber hypertrophy and that TM may be used to treat muscle wasting diseases. Our work not only suggests a novel druggable mechanism to increase muscle mass but also provides a tool for precisely regulating O₂^•- levels in vivo. Antioxid. Redox Signal. 42, 1-15.