title: Ibandronate concomitantly blocks immobilization-induced bone and muscle atrophy.
abstract: Both bone and muscle volume is concomitantly reduced under immobilization conditions; however, no single drug is currently available to block these outcomes simultaneously. Bisphosphonates are utilized clinically to inhibit osteoclast-dependent bone resorption, but their effects on muscle are largely unknown. Here we show that skeletal muscle is a direct target of the bisphosphonate ibandronate (IBN) and that reduced muscle volume and induction of Atrogin-1 and MuRF1, both atrogenes, are significantly inhibited by IBN administration in vivo using a mouse model of muscle atrophy. IBN treatment also significantly blocked immobilization-induced bone loss in vivo. We also report that expression of Atrogin-1 and MuRF1 and accumulation of Smad2/3 proteins, which are upstream of atrogines, occurred following serum starvation of myogenic C2C12 cells in vitro, effects significantly inhibited by IBN treatment. Interestingly, IBN effects on C2C12 cells were abrogated by MG132, an ubiquitin/proteasome inhibitor, suggesting that IBN functions via the ubiquitin-proteasome system. Our findings lend new insight into the role of IBN in preventing muscle atrophy.
authors.affiliation: Department of Orthopedic Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo, 160-8582, Japan.
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Watanabe
authors.affiliation: Department of Orthopedic Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo, 160-8582, Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Fujita
authors.affiliation: Product Research Department, Fuji Gotemba Research Laboratories, Chugai Pharmaceutical Co., Ltd, 1-135 Komakado, Gotemba, Shizuoka, 412-8513, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Takeda
authors.affiliation: Department of Orthopedic Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo, 160-8582, Japan; Department of Advanced Therapy for Musculoskeletal Disorders, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo, 160-8582, Japan.
authors.forename: Yuiko
authors.initials: Y
authors.lastname: Sato
authors.affiliation: Department of Orthopedic Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo, 160-8582, Japan; Department of Musculoskeletal Reconstruction and Regeneration Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo, 160-8582, Japan.
authors.forename: Tami
authors.initials: T
authors.lastname: Kobayashi
authors.affiliation: Division of Oral and Maxillofacial Surgery, Department of Dentistry and Oral Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo, 160-8582, Japan.
authors.forename: Mayu
authors.initials: M
authors.lastname: Morita
authors.affiliation: Department of Orthopedic Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo, 160-8582, Japan.
authors.forename: Takatsugu
authors.initials: T
authors.lastname: Oike
authors.affiliation: Department of Orthopedic Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo, 160-8582, Japan.
authors.forename: Kana
authors.initials: K
authors.lastname: Miyamoto
authors.affiliation: Product Research Department, Fuji Gotemba Research Laboratories, Chugai Pharmaceutical Co., Ltd, 1-135 Komakado, Gotemba, Shizuoka, 412-8513, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Matsumoto
authors.affiliation: Department of Orthopedic Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo, 160-8582, Japan.
authors.forename: Morio
authors.initials: M
authors.lastname: Matsumoto
authors.affiliation: Department of Orthopedic Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo, 160-8582, Japan.
authors.forename: Masaya
authors.initials: M
authors.lastname: Nakamura
authors.affiliation: Department of Orthopedic Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo, 160-8582, Japan; Department of Advanced Therapy for Musculoskeletal Disorders, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo, 160-8582, Japan. Electronic address: miyamoto@z5.keio.jp.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Miyamoto
mesh_terms: D000818:Animals; D050071:Bone Density Conservation Agents / Q000494:pharmacology; D001862:Bone Resorption / Q000209:etiology / Q000503:physiopathology* / Q000517:prevention & control*; D002460:Cell Line; D004164:Diphosphonates / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D000077557:Ibandronic Acid; D007103:Immobilization / Q000009:adverse effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D009133:Muscular Atrophy / Q000209:etiology / Q000503:physiopathology* / Q000517:prevention & control*; D009929:Organ Size / Q000187:drug effects; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D016896:Treatment Outcome; D054875:Ubiquitination / Q000187:drug effects
chemical_list: D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D046988:Proteasome Endopeptidase Complex; D000077557:Ibandronic Acid
keywords: Bisphosphonate; Bone loss; Ibandronate; Immobilization; Muscle atrophy; Osteoclast