Activation of cannabinoid type 2 receptor protects skeletal muscle from ischemia-reperfusion injury partly via Nrf2 signaling.

Cannabinoid type 2 (CB₂) receptor activation has been shown to attenuate IRI in various organs. NF-E2-related factor (Nrf2) is an anti-oxidative factor that plays multiple roles in regulating cellular redox homeostasis and modulating cell proliferation and differentiation. The protective effects of CB₂ receptor activation on skeletal muscle IRI and the underlying mechanism that involves Nrf2 signaling remain unknown.

We evaluated the in vivo effect of CB₂ receptor activation by the CB₂ receptor agonist AM1241 on IR-induced skeletal muscle damage and early myogenesis. We also assessed the effects of CB₂ receptor activation on C2C12 myoblasts differentiation and H₂O₂-induced C2C12 myoblasts damage in vitro, with a focus on the mechanism of Nrf2 signaling.

Our results showed that CB₂ receptor activation reduced IR-induced histopathological lesions, edema, and oxidative stress 1 day post-injury and accelerated early myogenesis 4 days post-injury in mice. Nrf2 knockout mice that were treated with AM1241 exhibited deteriorative skeletal muscle oxidative damage and myogenesis. In vitro, pretreatment with AM1241 significantly increased the expression of Nrf2 and its nuclear translocation, attenuated the decrease in H₂O₂-induced C2C12 cell viability, and decreased reactive oxygen species generation and apoptosis. CB₂ receptor activation also significantly enhanced C2C12 myoblasts differentiation, which was impaired by silencing Nrf2.

Overall, CB₂ receptor activation protected skeletal muscle against IRI by ameliorating oxidative damage and promoting early skeletal muscle myogenesis, which was partly via Nrf2 signaling.