title: Protective Effects of Clenbuterol against Dexamethasone-Induced Masseter Muscle Atrophy and Myosin Heavy Chain Transition.
abstract: BACKGROUND
  Glucocorticoid has a direct catabolic effect on skeletal muscle, leading to muscle atrophy, but no effective pharmacotherapy is available. We reported that clenbuterol (CB) induced masseter muscle hypertrophy and slow-to-fast myosin heavy chain (MHC) isoform transition through direct muscle β2-adrenergic receptor stimulation. Thus, we hypothesized that CB would antagonize glucocorticoid (dexamethasone; DEX)-induced muscle atrophy and fast-to-slow MHC isoform transition.
  
  
  METHODS
  We examined the effect of CB on DEX-induced masseter muscle atrophy by measuring masseter muscle weight, fiber diameter, cross-sectional area, and myosin heavy chain (MHC) composition. To elucidate the mechanisms involved, we used immunoblotting to study the effects of CB on muscle hypertrophic signaling (insulin growth factor 1 (IGF1) expression, Akt/mammalian target of rapamycin (mTOR) pathway, and calcineurin pathway) and atrophic signaling (Akt/Forkhead box-O (FOXO) pathway and myostatin expression) in masseter muscle of rats treated with DEX and/or CB.
  
  
  CONCLUSIONS
  Masseter muscle weight in the DEX-treated group was significantly lower than that in the Control group, as expected, but co-treatment with CB suppressed the DEX-induced masseter muscle atrophy, concomitantly with inhibition of fast-to-slow MHC isoforms transition. Activation of the Akt/mTOR pathway in masseter muscle of the DEX-treated group was significantly inhibited compared to that of the Control group, and CB suppressed this inhibition. DEX also suppressed expression of IGF1 (positive regulator of muscle growth), and CB attenuated this inhibition. Myostatin protein expression was unchanged. CB had no effect on activation of the Akt/FOXO pathway. These results indicate that CB antagonizes DEX-induced muscle atrophy and fast-to-slow MHC isoform transition via modulation of Akt/mTOR activity and IGF1 expression. CB might be a useful pharmacological agent for treatment of glucocorticoid-induced muscle atrophy.
authors.affiliation: Department of Physiology, Tsurumi University School of Dental Medicine, 230-8501, Yokohama, Japan; Department of Orthodontics, Tsurumi University School of Dental Medicine, 230-8501, Yokohama, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Umeki
authors.affiliation: Department of Physiology, Tsurumi University School of Dental Medicine, 230-8501, Yokohama, Japan.
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Ohnuki
authors.affiliation: Department of Physiology, Tsurumi University School of Dental Medicine, 230-8501, Yokohama, Japan.
authors.forename: Yasumasa
authors.initials: Y
authors.lastname: Mototani
authors.affiliation: Department of Physiology, Tsurumi University School of Dental Medicine, 230-8501, Yokohama, Japan.
authors.forename: Kouichi
authors.initials: K
authors.lastname: Shiozawa
authors.affiliation: Cardiovascular Research Institute, Yokohama City University Graduate School of Medicine, Yokohama, 236-0004, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Suita
authors.affiliation: Cardiovascular Research Institute, Yokohama City University Graduate School of Medicine, Yokohama, 236-0004, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Fujita
authors.affiliation: Department of Orthodontics, Tsurumi University School of Dental Medicine, 230-8501, Yokohama, Japan.
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Nakamura
authors.affiliation: Department of Physiology, Tsurumi University School of Dental Medicine, 230-8501, Yokohama, Japan.
authors.forename: Yasutake
authors.initials: Y
authors.lastname: Saeki
authors.affiliation: Department of Physiology, Tsurumi University School of Dental Medicine, 230-8501, Yokohama, Japan; Cardiovascular Research Institute, Yokohama City University Graduate School of Medicine, Yokohama, 236-0004, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Okumura
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002976:Clenbuterol / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D003907:Dexamethasone / Q000494:pharmacology; D004734:Energy Metabolism / Q000187:drug effects; D005247:Feeding Behavior / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D006984:Hypertrophy / Q000188:drug therapy / Q000473:pathology; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008406:Masseter Muscle / Q000002:abnormalities / Q000187:drug effects / Q000473:pathology*; D009124:Muscle Proteins / Q000378:metabolism; D009133:Muscular Atrophy / Q000188:drug therapy* / Q000473:pathology; D018995:Myosin Heavy Chains / Q000378:metabolism*; D009929:Organ Size / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D010768:Phosphoserine / Q000378:metabolism; D020011:Protective Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D020033:Protein Isoforms / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017208:Rats, Wistar; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D009124:Muscle Proteins; D020011:Protective Agents; D020033:Protein Isoforms; D012333:RNA, Messenger; D018343:Receptors, Adrenergic, beta-2; D011965:Receptors, Glucocorticoid; D010768:Phosphoserine; D007334:Insulin-Like Growth Factor I; D003907:Dexamethasone; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D018995:Myosin Heavy Chains; D002976:Clenbuterol