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1 Regeneron Pharmaceuticals, Tarrytown, New York, United States
2 Neurobiology, Physiology & Behavior, University of California, Davis, Davis, California, United States
3 NPB, UC Davis, One Shields Ave, Davis, California, 95616, United States; Regeneron Pharmaceuticals, Tarrytown, New York, United States
* To whom correspondence should be addressed. E-mail: scbodine{at}ucdavis.edu.
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/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 the mammalian target of rapamycin (mTOR) was involved in mediating the effects of clenbuterol. Clenbuterol administration increased the phosphorylation status of PKB/Akt, S6K1/p70s6k, and 4E-BP1/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 following 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.
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