title: Establishment of a novel mouse model for pioglitazone-induced skeletal muscle injury.
abstract: 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.
authors.affiliation: Department of Drug Safety Sciences, Division of Clinical Pharmacology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan. Electronic address: akaisho@med.nagoya-u.ac.jp.
authors.forename: Sho
authors.initials: S
authors.lastname: Akai
authors.affiliation: Department of Drug Safety Sciences, Division of Clinical Pharmacology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan. Electronic address: shingo61@med.nagoya-u.ac.jp.
authors.forename: Shingo
authors.initials: S
authors.lastname: Oda
authors.affiliation: Department of Drug Safety Sciences, Division of Clinical Pharmacology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan. Electronic address: tyokoi@med.nagoya-u.ac.jp.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Yokoi
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D003402:Creatine Kinase / Q000097:blood; D004195:Disease Models, Animal; D005260:Female; D005978:Glutathione / Q000037:antagonists & inhibitors*; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D035683:MicroRNAs / Q000097:blood; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000293:injuries / Q000378:metabolism; D009135:Muscular Diseases / Q000097:blood / Q000139:chemically induced* / Q000378:metabolism; D000077205:Pioglitazone; D045162:Thiazolidinediones
chemical_list: D035683:MicroRNAs; C540669:Mirn206 microRNA, mouse; D045162:Thiazolidinediones; D019328:Buthionine Sulfoximine; D000255:Adenosine Triphosphate; D001219:Aspartate Aminotransferases; D003402:Creatine Kinase; D005978:Glutathione; D000077205:Pioglitazone
keywords: Drug-induced skeletal muscle injury; Mouse; Oxidative stress; Pioglitazone; microRNA