Rapamycin inhibits the growth and muscle-sparing effects of clenbuterol.
Clenbuterol and other beta2-adrenergic agonists are effective at inducing muscle growth and attenuating muscle atrophy through unknown mechanisms. This study tested the hypothesis that clenbuterol-induced growth and muscle sparing is mediated through the activation of Akt and mammalian target of rapamycin (mTOR) signaling pathways. Clenbuterol was administered to normal weight-bearing adult rats to examine the growth-inducing effects and to adult rats undergoing muscle atrophy as the result of hindlimb suspension or denervation to examine the muscle-sparing effects. The pharmacological inhibitor rapamycin was administered in combination with clenbuterol in vivo to determine whether activation of mTOR was involved in mediating the effects of clenbuterol. Clenbuterol administration increased the phosphorylation status of PKB/Akt, S6 kinase 1/p70(s6k), and eukaryotic initiation factor 4E binding protein 1/PHAS-1. Clenbuterol treatment induced growth by 27-41% in normal rats and attenuated muscle loss during hindlimb suspension by 10-20%. Rapamycin treatment resulted in a 37-97% suppression of clenbuterol-induced growth and a 100% reduction of the muscle-sparing effect. In contrast, rapamycin was unable to block the muscle-sparing effects of clenbuterol after denervation. Clenbuterol was also shown to suppress the expression of the MuRF1 and MAFbx transcripts in muscles from normal, denervated, and hindlimb-suspended rats. These results demonstrate that the effects of clenbuterol are mediated, in part, through the activation of Akt and mTOR signaling pathways.
Kline
William O
WO
Univ. of California, Davis, Section of Neurobiology, Physiology, and Behavior, One Shields Ave., Davis, California 95616, USA.
Panaro
Frank J
FJ
Yang
Hayung
H
Bodine
Sue C
SC
D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D002976:Clenbuterol / Q000494:pharmacology*; D004347:Drug Interactions; D005260:Female; D019417:Hindlimb Suspension; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D009124:Muscle Proteins / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects / Q000254:growth & development*; D009133:Muscular Atrophy / Q000503:physiopathology / Q000517:prevention & control*; D011494:Protein Kinases / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044843:SKP Cullin F-Box Protein Ligases / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
D000318:Adrenergic beta-Agonists; D007166:Immunosuppressive Agents; D009124:Muscle Proteins; D000070584:Tripartite Motif Proteins; C486692:Fbxo32 protein, rat; D044843:SKP Cullin F-Box Protein Ligases; C499086:Trim63 protein, rat; D044767:Ubiquitin-Protein Ligases; D011494:Protein Kinases; C546845:mTOR protein, rat; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus; D002976:Clenbuterol