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Am J Physiol Endocrinol Metab (June 24, 2008). doi:10.1152/ajpendo.90411.2008 Free Article
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Submitted on May 1, 2008
Revised on June 19, 2008
Accepted on June 21, 2008

Disassociation between the effects of amino acids and insulin on signalling, ubiquitin-ligases and protein turnover in human muscle

Paul L. Greenhaff1*, Leonidas Karagounis, Nicholas Peirce, Elizabeth J Simpson, Michelle Hazell, Robert Layfield, Henning Wackerhage2, Kenneth Smith3, Philip Atherton, Anna Selby, and Michael J. Rennie3

1 University of Nottingham Medical School
2 Univeristy of Dundee
3 University of Nottingham

* To whom correspondence should be addressed. E-mail: paul.greenhaff{at}nottingham.ac.uk.

We determined the effects of intravenous infusion of amino acids (AA) at serum insulin concentrations of 5, 30, 72 and 167 mU/l-1 on anabolic signalling, expression of ubiquitin-proteasome components and protein turnover in muscles of healthy, young men. Tripling AA availability at 5 mU/l-1 insulin, doubled the 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). Increasing serum insulin concentration from 5 to 30 mU/l-1, while keeping AA availability constant, halved LPB (P<0.05) without further inhibition of LPB at higher insulin doses, whereas rates of MPS were identical to that at 5 mU/l-1 insulin. The phosphorylation of PKBSer473 and p70S6k Thr389k increased concomitantly with insulin availability; however while raising insulin to 30 mU/l-1 increased the phosphorylation of mTORSer2448,4E-BP1Thr37/46, and GSK3{beta} Ser9, and decreased that of eEF2Thr56, higher insulin doses to 72 and 167 mU/l-1 did not augment these responses. MAFbx and proteasome C2 subunit protein expression declined as insulin increased, with MuRF-1 expression largely unchanged. Thus, increasing AA and insulin availability causes changes in anabolic signalling and amounts of enzymes of the ubiquitin-proteasome pathway which cannot be easily reconciled with observed effects on MPS or LPB.




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