Mitochondrial fission contributes to heat-induced oxidative stress in skeletal muscle but not hyperthermia in mice

Aims: We have previously demonstrated in vitro that heat-induced skeletal muscle damage is associated with an increase in dynamin-related protein 1 (Drp1)-mediated mitochondrial fission and no change in mitochondrial fusion. In this study, we investigated the in vivo effects of mitochondrial fission inhibition on heat-induced oxidative skeletal muscle injury and hyperthermic response in mice. Main methods: Core body temperatures of mice pre-treated with vehicle or Mdivi-1 were recorded by radio telemetry during heat exposure. Tissue samples were obtained immediately following heat exposure. Key findings: We found that heat exposure caused increased mitochondrial fragmentation and mitochondrial fission protein Drp1 expression, whereas had no effect on the mitochondrial fusion-related proteins mitofusin 1, mitofusin 2 and OPA1 in mouse gastrocnemius muscles. Two groups of mice with a similar high level of heat-induced hyperthermia were allowed to recover for at least one week and subsequently treated with Mdivi-1 and vehicle, respectively. Neither Mdivi-1 nor vehicle altered the hyperthermic responses of mice during heat exposure. However, Mdivi-1 significantly reduced mitochondrial fragmentation and Drp1, reactive oxygen species levels and apoptotic responses in mouse gastrocnemius muscles following heat exposure compared with vehicle. Significance: These results suggest that Drp1-mediated mitochondrial fission plays a role in heat-induced oxidative stress in skeletal muscle, but not in hyperthermic response in mice.