The cannabinoid receptor 1 antagonist AM6545 stimulates the Akt-mTOR axis and in vivo muscle protein synthesis in a dexamethasone-induced muscle atrophy model

Cannabinoid receptor 1 (CB1) antagonists were shown to stimulate in vitro muscle protein synthesis, but this has never been confirmed in vivo. Therefore, this study investigated whether treatment with the CB1 antagonist AM6545 upregulates in vivo muscle anabolism. Chronic AM6545 treatment stimulated the Akt-mTOR axis and protein synthesis (+22%; p = 0.002) in the Tibialis Anterior, which protected mice from dexamethasone-induced muscle loss (−1% vs. −6% compared to healthy controls; p = 0.02). Accordingly, acute AM6545 treatment stimulated protein synthesis (+44%; p = 0.04) in the Tibialis Anterior but not Soleus. The anabolic upregulation was accompanied by ERK1/2 activation, whereas protein kinase A signaling remained unaffected, suggesting a CB1-independent mechanism. The present study for the first time shows that the CB1 antagonist AM6545 can upregulate the Akt-mTOR axis and in vivo muscle protein synthesis. However, future work applying genetic approaches should further uncover the signaling pathways via which AM6545 enhances muscle anabolism. •Cannabiniod receptor 1 (CB1) antagonist AM6545 stimulates in vivo muscle protein synthesis.•AM6545 activates Akt-mTORC1 signaling.•AM6545 protects mice from dexamethasone-induced muscle loss.•CB1 antagonism is a promising strategy to attenuate anabolic resistance.