title: Skeletal muscle-specific HMG-CoA reductase knockout mice exhibit rhabdomyolysis: A model for statin-induced myopathy.
abstract: HMG-CoA reductase (HMGCR) catalyzes the conversion of HMG-CoA to mevalonic acid (MVA); this is the rate-limiting enzyme of the mevalonate pathway that synthesizes cholesterol. Statins, HMGCR inhibitors, are widely used as cholesterol-reducing drugs. However, statin-induced myopathy is the most adverse side effect of statins. To eludicate the mechanisms underlying statin the myotoxicity and HMGCR function in the skeletal muscle, we developed the skeletal muscle-specific HMGCR knockout mice. Knockout mice exhibited postnatal myopathy with elevated serum creatine kinase levels and necrosis. Myopathy in knockout mice was completely rescued by the oral administration of MVA. These results suggest that skeletal muscle toxicity caused by statins is dependent on the deficiencies of HMGCR enzyme activity and downstream metabolites of the mevalonate pathway in skeletal muscles rather than the liver or other organs.
authors.affiliation: Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan; Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Osaki
authors.affiliation: Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan; International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan.
authors.forename: Yoshimi
authors.initials: Y
authors.lastname: Nakagawa
authors.affiliation: Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan.
authors.forename: Shoko
authors.initials: S
authors.lastname: Miyahara
authors.affiliation: Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Iwasaki
authors.affiliation: Department of Neurology, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Ishii
authors.affiliation: Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Matsuzaka
authors.affiliation: Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan.
authors.forename: Kazuto
authors.initials: K
authors.lastname: Kobayashi
authors.affiliation: Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Yatoh
authors.affiliation: Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan.
authors.forename: Akimitsu
authors.initials: A
authors.lastname: Takahashi
authors.affiliation: Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan.
authors.forename: Naoya
authors.initials: N
authors.lastname: Yahagi
authors.affiliation: Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Suzuki
authors.affiliation: Department of Hematology, Endocrinology and Metabolism, Niigata University Faculty of Medicine, Niigata, Niigata 951-8510, Japan.
authors.forename: Hirohito
authors.initials: H
authors.lastname: Sone
authors.affiliation: Department of General Internal Medicine, Dentistry, and Oncologic Emergencies, National Cancer Center Hospital, Chuo Ward, Tokyo 104-0045, Japan.
authors.forename: Ken
authors.initials: K
authors.lastname: Ohashi
authors.affiliation: Division of Endocrinology and Metabolism, School of Medicine, Jichi Medical University, Shimotsuke, Tochigi 329-0498, Japan.
authors.forename: Shun
authors.initials: S
authors.lastname: Ishibashi
authors.affiliation: Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan.
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Yamada
authors.affiliation: Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan; International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan. Electronic address: hshimano@md.tsukuba.ac.jp.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Shimano
mesh_terms: D000818:Animals; D002784:Cholesterol / Q000378:metabolism; D003402:Creatine Kinase / Q000097:blood; D004195:Disease Models, Animal; D006903:Hydroxymethylglutaryl CoA Reductases / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000009:adverse effects*; D008297:Male; D008798:Mevalonic Acid / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000201:enzymology*; D009135:Muscular Diseases / Q000139:chemically induced / Q000201:enzymology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012206:Rhabdomyolysis / Q000201:enzymology* / Q000209:etiology*
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D012333:RNA, Messenger; D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases; D003402:Creatine Kinase; D008798:Mevalonic Acid
keywords: HMG-CoA reductase; Knockout mice; Mevalonic acid; Necrosis; Rhabdomyolysis; Skeletal muscle