Eicosapentaenoic acid attenuates statin-induced ER stress and toxicity in myoblast

Abstract We previously reported that eicosapentaenoic acid (EPA) improved statin-induced rhabdomyolysis in rats (Naba et al. [6] ). In this study, we report for the first time direct improvement by EPA of statin-induced toxicity in cultured myoblasts and the mechanistic involvement of endoplasmic reticulum (ER) stress. Differentiated rhabdomyosarcoma cells (RD cells) were treated with statins and EPA for 1–4 days. Statins induced various toxic changes in RD cells, and EPA attenuated all of these changes. Interestingly, statins increased mRNA expression of ER stress markers (XBP-1 and CHOP) and EPA attenuated both. Further, in a statin-induced rat model of rhabdomyolysis, these markers in skeletal muscle were significantly correlated with plasma CPK activity. In RD cells, statins also increased p-c-Jun protein content and caspase-3/7 activity, while 4-PBA, an ER stress attenuator, PPAR-δ agonist, and EPA attenuated them. These findings suggest that EPA attenuates statin-induced ER stress, JNK activation and toxicity in cultured myoblast cells, and that PPAR-δ may mechanically involved in the effects of EPA.