Establishment of a novel mouse model for pioglitazone-induced skeletal muscle injury

Skeletal muscle (SKM) injury is one of the major safety concerns in risk assessment for drug development. However, no appropriate pre-clinical animal model exists to evaluate drug-induced SKM injury except that caused by fibrates and statins. Thiazolidinedione, a PPARγ agonistic drug for type 2 diabetes mellitus, is widely used clinically but can induce adverse effects such as hepatotoxicity and SKM injury, as has been reported in recent decades. Moreover, thiazolidinedione-induced SKM injury has only been reported in humans, and no evidence of SKM injury has been observed in rodents. To establish a drug-induced SKM injury mouse model, we administered pioglitazone with a glutathione biosynthesis inhibitor, L-buthionine-S,R-sulfoximine, to C57BL/6J mice for 2days and subsequently observed prominent increases in plasma aspartate aminotransferase and creatinine phosphokinase, which were associated with SKM lesions. Furthermore, plasma miR-206 (SKM-specific microRNA) level was significantly increased, whereas plasma miR-208 (heart-specific microRNA) was not detected, indicating that pioglitazone specifically caused SKM, not cardiac, injury. Furthermore, we revealed that pioglitazone-induced SKM injury was caused by oxidative stress that was independent of the PPARγ agonistic effect. This study demonstrated for the first time that the glutathione-depleted C57BL/6J mouse is a novel model for assessing drug-induced SKM injury in drug development.