Rapamycin inhibits the growth and muscle-sparing effects of clenbuterol

• Published in: Journal of applied physiology (1985) Vol. 102; no. 2; pp. 740 - 747
• Main Authors: Kline, William O, Panaro, Frank J, Yang, Hayung, Bodine, Sue C
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Am Physiological Soc 01.02.2007; American Physiological Society
• Subjects: Adrenergic beta-Agonists - pharmacology; Animals; Biological and medical sciences; Clenbuterol - pharmacology; Drug Interactions; Drugs; Female; Fundamental and applied biological sciences. Psychology; Hindlimb Suspension; Immunosuppressive Agents - pharmacology; Kinases; Mammals; Muscle Proteins - metabolism; Muscle, Skeletal - drug effects; Muscle, Skeletal - growth & development; Muscular Atrophy - physiopathology; Muscular Atrophy - prevention & control; Muscular system; Protein Kinases - physiology; Proto-Oncogene Proteins c-akt - physiology; Rats; Rats, Sprague-Dawley; Signal Transduction - physiology; Sirolimus - pharmacology; SKP Cullin F-Box Protein Ligases - metabolism; TOR Serine-Threonine Kinases; Tripartite Motif Proteins; Ubiquitin-Protein Ligases - metabolism; Agonist; MaFBx; Sirolimus; Growth; Akt/PKB; MuRF1; Lactone; β2-Adrenergic receptor; Clenbuterol; Striated muscle; Macrolide; Macrocycle; β2-adrenergic agonists; Vertebrata; Mammalia; mTOR; Protein synthesis inhibitor
• ISSN: 8750-7587; 1522-1601
• DOI: 10.1152/japplphysiol.00873.2006

1 Section of Neurobiology, Physiology & Behavior, University of California, Davis, California; and 2 Regeneron Pharmaceuticals, Tarrytown, New York Submitted 7 August 2006 ; accepted in final form 15 October 2006 Clenbuterol and other 2 -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. 2 -adrenergic agonists; mTOR; Akt/PKB; MuRF1; MaFBx Address for reprint requests and other correspondence: S. C. Bodine, Univ. of California, Davis, Section of Neurobiology, Physiology, and Behavior, 196 Briggs Hall, One Shields Ave., Davis, California 95616 (e-mail: scbodine{at}ucdavis.edu )