MicroRNA-mediated repression of endocannabinoid CB1 receptor expression contributes to simvastatin-induced skeletal muscle toxicity

Abstract

Abstract Statins are the most prescribed lipid-lowering agents worldwide. Their use is generally safe, although muscular toxicity occurs in 1 in 10.000 patients. In this study, we explored the role of the endocannabinoid system (ECS) during muscle toxicity induced by simvastatin. In murine C2C12 myoblasts exposed to simvastatin (30 µM), we found that the levels of the endocannabinoids 2-AG and AEA as well the expression of specific miRNAs (mostly miR-152) targeting the endocannabinoid CB1 gene were increased. Rimonabant, a selective CB1 antagonist, exacerbated simvastatin-induced toxicity in myoblasts, while the opposite effect was observed with GAT211, a CB1-positive allosteric modulator. In antagomiR-152-transfected myoblasts, simvastatin toxicity was prevented along with the rescue of CB1 expression. Notably, similar alterations were found in skeletal muscles of C57BL/6J mice treated with simvastatin 20 mg Kg-1 and in primary human myoblasts. In sum, we identified the ECS as a novel mechanism participating in statin-induced myopathy.