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Am J Physiol Endocrinol Metab 295: E595-E604, 2008. First published June 24, 2008; doi:10.1152/ajpendo.90411.2008 Free Article
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Disassociation between the effects of amino acids and insulin on signaling, ubiquitin ligases, and protein turnover in human muscle

P. L. Greenhaff,1,2 L. G. Karagounis,1,2 N. Peirce,1,2 E. J. Simpson,1,2 M. Hazell,1,2 R. Layfield,1,2 H. Wackerhage,4 K. Smith,1,3 P. Atherton,1,3 A. Selby,1,3 and M. J. Rennie1,3

1Centre for Integrated Systems Biology and Medicine, 2School of Biomedical Sciences, and 3School of Graduate Entry Medicine and Health, University of Nottingham, Nottingham; and 4Institute of Medical Sciences, University of Aberdeen, Aberdeen, United Kingdom

Submitted 1 May 2008 ; accepted in final form 21 June 2008

We determined the effects of intravenous infusion of amino acids (AA) at serum insulin of 5, 30, 72, and 167 mU/l on anabolic signaling, expression of ubiquitin-proteasome components, and protein turnover in muscles of healthy young men. Tripling AA availability at 5 mU/l insulin doubled incorporation of [1-13C]leucine [i.e., muscle protein synthesis (MPS), P < 0.01] without affecting the rate of leg protein breakdown (LPB; appearance of d5-phenylalanine). While keeping AA availability constant, increasing insulin to 30 mU/l halved LPB (P < 0.05) without further inhibition at higher doses, whereas rates of MPS were identical to that at 5 mU/l insulin. The phosphorylation of PKB Ser473 and p70S6k Thr389 increased concomitantly with insulin, but whereas raising insulin to 30 mU/l increased the phosphorylation of mTOR Ser2448, 4E-BP1 Thr37/46, or GSK3β Ser9 and decreased that of eEF2 Thr56, higher insulin doses to 72 and 167 mU/l did not augment these latter responses. MAFbx and proteasome C2 subunit proteins declined as insulin increased, with MuRF-1 expression largely unchanged. Thus increasing AA and insulin availability causes changes in anabolic signaling and amounts of enzymes of the ubiquitin-proteasome pathway, which cannot be easily reconciled with observed effects on MPS or LPB.

muscle protein synthesis; muscle protein breakdown


Address for reprint requests and other correspondence: P. Greenhaff, School of Biomedical Sciences, Centre for Integrated Systems Biology and Medicine, Univ. of Nottingham, Queen's Medical Centre, Nottingham NG7 2UH, UK (e-mail: paul.greenhaff{at}nottingham.ac.uk), or M. J. Rennie, School of Graduate Entry Medicine and Health, Centre for Integrated Systems Biology and Medicine, City Hospital, Uttoxeter Rd., Derby DE22 3DT, UK (e-mail: michael.rennie{at}nottingham.ac.uk)




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