title: Smad2/3 Proteins Are Required for Immobilization-induced Skeletal Muscle Atrophy.
abstract: Skeletal muscle atrophy promotes muscle weakness, limiting activities of daily living. However, mechanisms underlying atrophy remain unclear. Here, we show that skeletal muscle immobilization elevates Smad2/3 protein but not mRNA levels in muscle, promoting atrophy. Furthermore, we demonstrate that myostatin, which negatively regulates muscle hypertrophy, is dispensable for denervation-induced muscle atrophy and Smad2/3 protein accumulation. Moreover, muscle-specific Smad2/3-deficient mice exhibited significant resistance to denervation-induced muscle atrophy. In addition, expression of the atrogenes Atrogin-1 and MuRF1, which underlie muscle atrophy, did not increase in muscles of Smad2/3-deficient mice following denervation. We also demonstrate that serum starvation promotes Smad2/3 protein accumulation in C2C12 myogenic cells, an in vitro muscle atrophy model, an effect inhibited by IGF1 treatment. In vivo, we observed IGF1 receptor deactivation in immobilized muscle, even in the presence of normal levels of circulating IGF1. Denervation-induced muscle atrophy was accompanied by reduced glucose intake and elevated levels of branched-chain amino acids, effects that were Smad2/3-dependent. Thus, muscle immobilization attenuates IGF1 signals at the receptor rather than the ligand level, leading to Smad2/3 protein accumulation, muscle atrophy, and accompanying metabolic changes.
authors.affiliation: From the Departments of Orthopedic Surgery.
authors.forename: Toshimi
authors.initials: T
authors.lastname: Tando
authors.affiliation: the Institute for Advanced Biosciences, Keio University, 246-2 Mizukami, Kakuganji, Tsuruoka, Yamagata 997-0052, and.
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Hirayama
authors.affiliation: From the Departments of Orthopedic Surgery.
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Furukawa
authors.affiliation: From the Departments of Orthopedic Surgery, Musculoskeletal Reconstruction and Regeneration Surgery.
authors.forename: Yuiko
authors.initials: Y
authors.lastname: Sato
authors.affiliation: From the Departments of Orthopedic Surgery, Musculoskeletal Reconstruction and Regeneration Surgery.
authors.forename: Tami
authors.initials: T
authors.lastname: Kobayashi
authors.affiliation: From the Departments of Orthopedic Surgery.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Funayama
authors.affiliation: From the Departments of Orthopedic Surgery.
authors.forename: Arihiko
authors.initials: A
authors.lastname: Kanaji
authors.affiliation: From the Departments of Orthopedic Surgery.
authors.forename: Wu
authors.initials: W
authors.lastname: Hao
authors.affiliation: From the Departments of Orthopedic Surgery.
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Watanabe
authors.affiliation: Dentistry and Oral Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582.
authors.forename: Mayu
authors.initials: M
authors.lastname: Morita
authors.affiliation: From the Departments of Orthopedic Surgery.
authors.forename: Takatsugu
authors.initials: T
authors.lastname: Oike
authors.affiliation: From the Departments of Orthopedic Surgery.
authors.forename: Kana
authors.initials: K
authors.lastname: Miyamoto
authors.affiliation: the Institute for Advanced Biosciences, Keio University, 246-2 Mizukami, Kakuganji, Tsuruoka, Yamagata 997-0052, and.
authors.forename: Tomoyoshi
authors.initials: T
authors.lastname: Soga
authors.affiliation: the Department of Medicine and Bioregulatory Science, Graduate School of Medical Science, Kyushu University, Maidashi 3-1-1, Higashi Ward, Fukuoka 812-8582, Japan.
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Nomura
authors.affiliation: Immunology, and.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Yoshimura
authors.affiliation: the Institute for Advanced Biosciences, Keio University, 246-2 Mizukami, Kakuganji, Tsuruoka, Yamagata 997-0052, and.
authors.forename: Masaru
authors.initials: M
authors.lastname: Tomita
authors.affiliation: From the Departments of Orthopedic Surgery.
authors.forename: Morio
authors.initials: M
authors.lastname: Matsumoto
authors.affiliation: From the Departments of Orthopedic Surgery.
authors.forename: Masaya
authors.initials: M
authors.lastname: Nakamura
authors.affiliation: From the Departments of Orthopedic Surgery.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Toyama
authors.affiliation: From the Departments of Orthopedic Surgery, miyamoto@z5.keio.jp.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Miyamoto
mesh_terms: D000597:Amino Acids, Branched-Chain / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D005947:Glucose / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000378:metabolism / Q000494:pharmacology; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009121:Muscle Denervation; D018485:Muscle Fibers, Skeletal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D018482:Muscle, Skeletal / Q000294:innervation / Q000378:metabolism* / Q000473:pathology; D009133:Muscular Atrophy / Q000209:etiology / Q000378:metabolism*; D055435:Myostatin / Q000235:genetics / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism; D012149:Restraint, Physical / Q000009:adverse effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D044843:SKP Cullin F-Box Protein Ligases / Q000235:genetics / Q000378:metabolism; D051899:Smad2 Protein / Q000235:genetics / Q000378:metabolism*; D051900:Smad3 Protein / Q000235:genetics / Q000378:metabolism*; D000070584:Tripartite Motif Proteins / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism
chemical_list: D000597:Amino Acids, Branched-Chain; D009124:Muscle Proteins; D055435:Myostatin; D051899:Smad2 Protein; D051900:Smad3 Protein; D000070584:Tripartite Motif Proteins; D007334:Insulin-Like Growth Factor I; C486691:Fbxo32 protein, mouse; D044843:SKP Cullin F-Box Protein Ligases; C499084:Trim63 protein, mouse; D044767:Ubiquitin-Protein Ligases; D017526:Receptor, IGF Type 1; D005947:Glucose
keywords: SMAD transcription factor; metabolism; muscle; muscle atrophy; myostatin