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 (KBP-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-delta 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-delta may mechanically involved in the effects of EPA. (C) 2012 Elsevier Inc. All rights reserved.