Rapamycin inhibits the growth and muscle-sparing effects of clenbuterol

Journal of Applied Physiology - Tập 102 Số 2 - Trang 740-747 - 2007
William O. Kline1, Frank J. Panaro2, Hayung Yang3, Sue C. Bodine4
1Univ. of California, Davis, Section of Neurobiology, Physiology, and Behavior, One Shields Ave., Davis, California 95616, USA.
2Regeneron Pharmaceuticals, Inc
3University Of California at Davis#TAB#
4Physiology and Membrane Biology

Tóm tắt

Clenbuterol and other β2-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/p70s6k, 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.

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Tài liệu tham khảo

10.1016/0300-9629(92)90026-M

10.2170/jjphysiol.53.229

Apseloff G, Girten B, Walker M, Shepard DR, Krecic ME, Stern LS, Gerber N. Aminohydroxybutane bisphosphonate and clenbuterol prevent bone changes and retard muscle atrophy respectively in tail-suspended rats. J Pharmacol Exp Ther 264: 1071–1078, 1993.

10.1111/j.1432-1033.1980.tb06030.x

10.1074/jbc.271.9.5033

Babij P, Booth FW. Clenbuterol prevents or inhibits loss of specific mRNAs in atrophying rat skeletal muscle. Am J Physiol Cell Physiol 254: C657–C660, 1988.

10.1126/science.1065874

10.1038/ncb1101-1014

10.1152/ajpendo.1992.263.1.E50

10.1002/mus.1200

10.1172/JCI117929

Dodd SL, Koesterer TJ. Clenbuterol attenuates muscle atrophy and dysfunction in hindlimb-suspended rats. Aviat Space Environ Med 73: 635–639, 2002.

10.1038/sj.onc.1207542

10.1152/ajpregu.1994.267.1.R316

10.1152/japplphysiol.01203.2005

10.1016/j.semcdb.2003.12.017

Harris TE, Lawrence JC Jr. TOR signaling. Sci STKE 2003: re15, 2003.

10.1016/0742-8413(92)90037-8

10.1002/mus.20416

10.1002/mus.10092

10.1042/bj2720831

Kim YS, Lee YB, Ashmore CR. Cimaterol-induced growth in rats: growth pattern and biochemical characteristics. Growth Dev Aging 52: 41–45, 1988.

10.1016/0024-3205(92)90374-X

10.1152/japplphysiol.00221.2002

10.1212/WNL.57.8.1434

10.1042/bj2640573

10.1002/mus.880150809

10.1007/BF01116510

Maltin CA, Hay SM, McMillan DN, Delday MI. Tissue specific responses to clenbuterol: temporal changes in protein metabolism of striated muscle and visceral tissues from rats. Growth Regul 2: 161–166, 1992.

10.2527/1998.761160x

10.3181/00379727-221-44402

10.1016/j.biocel.2005.02.026

10.1152/ajpendo.2000.279.3.E663

10.1016/j.cellsig.2004.09.001

10.1079/BJN19860104

10.1146/annurev.physiol.66.052102.134444

Roberts P, McGeachie JK. The effects of clenbuterol on satellite cell activation and the regeneration of skeletal muscle: an autoradiographic and morphometric study of whole muscle transplants in mice. J Anat 180: 57–65, 1992.

10.1152/ajpregu.00324.2002

10.1113/jphysiol.2003.056770

10.1016/S0092-8674(04)00400-3

Sartorelli V, Fulco M. Molecular and cellular determinants of skeletal muscle atrophy and hypertrophy. Sci STKE 2004: re11, 2004.

10.1016/S0003-9993(95)80043-3

10.1152/ajpendo.2000.279.1.E188

10.1152/ajpendo.2001.281.4.E676

10.1016/S1097-2765(04)00211-4

10.1159/000063712

Xiao RP. β-Adrenergic signaling in the heart: dual coupling of the β2-adrenergic receptor to G(s) and G(i) proteins. Sci STKE 2001: RE15, 2001.

10.1152/japplphysiol.00448.2004

10.1152/ajpendo.1987.252.1.E152

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Journal of Applied Physiology

Tập 102 Số 2

740-747

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