title: Clenbuterol, a β2-adrenergic agonist, reciprocally alters PGC-1 alpha and RIP140 and reduces fatty acid and pyruvate oxidation in rat skeletal muscle.
abstract: Clenbuterol, a β2-adrenergic agonist, reduces mitochondrial content and enzyme activities in skeletal muscle, but the mechanism involved has yet to be identified. We examined whether clenbuterol-induced changes in the muscles' metabolic profile and the intrinsic capacity of mitochondria to oxidize substrates are associated with reductions in the nuclear receptor coactivator PGC-1 alpha and/or an increase in the nuclear corepressor RIP140. In rats, clenbuterol was provided in the drinking water (30 mg/l). In 3 wk, this increased body (8%) and muscle weights (12-17%). In red (R) and white (W) muscles, clenbuterol induced reductions in mitochondrial content (citrate synthase: R, 27%; W, 52%; cytochrome-c oxidase: R, 24%; W, 34%), proteins involved in fatty acid transport (fatty acid translocase/CD36: R, 36%; W, 35%) and oxidation [β-hydroxyacyl CoA dehydrogenase (β-HAD): R, 33%; W, 62%], glucose transport (GLUT4: R, 8%; W, 13%), lactate transport monocarboxylate transporter (MCT1: R, 61%; W, 37%), and pyruvate oxidation (PDHE1α, R, 18%; W, 12%). Concurrently, only red muscle lactate dehydrogenase activity (25%) and MCT4 (31%) were increased. Palmitate oxidation was reduced in subsarcolemmal (SS) (R, 30%; W, 52%) and intermyofibrillar (IMF) mitochondria (R, 17%; W, 44%) along with reductions in β-HAD activity (SS: R, 17%; W, 51%; IMF: R, 20%; W, 57%). Pyruvate oxidation was only reduced in SS mitochondria (R, 20%; W, 28%), but this was not attributable solely to PDHE1α, which was reduced in both SS (R, 21%; W, 20%) and IMF mitochondria (R, 15%; W, 43%). These extensive metabolic changes induced by clenbuterol were associated with reductions in PGC-1α (R, 37%; W, 32%) and increases in RIP140 (R, 23%; W, 21%). This is the first evidence that clenbuterol appears to exert its metabolic effects via simultaneous and reciprocal changes in the nuclear receptor coactivator PGC-1α and the nuclear corepressor RIP140.
authors.affiliation: Department of Sports Sciences, The University of Tokyo, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Hoshino
authors.forename: Yuko
authors.initials: Y
authors.lastname: Yoshida
authors.forename: Graham P
authors.initials: GP
authors.lastname: Holloway
authors.forename: James
authors.initials: J
authors.lastname: Lally
authors.forename: Hideo
authors.initials: H
authors.lastname: Hatta
authors.forename: Arend
authors.initials: A
authors.lastname: Bonen
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000187:drug effects / Q000378:metabolism*; D058666:Adrenergic beta-2 Receptor Agonists / Q000494:pharmacology*; D000818:Animals; D002976:Clenbuterol / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects; D005227:Fatty Acids / Q000378:metabolism*; D008297:Male; D008931:Mitochondria, Muscle / Q000187:drug effects / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000187:drug effects / Q000378:metabolism; D023421:Models, Animal; D009124:Muscle Proteins / Q000187:drug effects / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism*; D009687:Nuclear Proteins / Q000187:drug effects / Q000378:metabolism*; D000078723:Nuclear Receptor Interacting Protein 1; D010084:Oxidation-Reduction; D010168:Palmitates / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011773:Pyruvates / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014157:Transcription Factors / Q000187:drug effects / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D058666:Adrenergic beta-2 Receptor Agonists; D005227:Fatty Acids; D024101:Mitochondrial Proteins; D009124:Muscle Proteins; D009687:Nuclear Proteins; D000078723:Nuclear Receptor Interacting Protein 1; D010168:Palmitates; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C501429:Ppargc1a protein, rat; D011773:Pyruvates; D016601:RNA-Binding Proteins; D014157:Transcription Factors; D002976:Clenbuterol