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Increased Plasma TNFα Together with Higher Cellular Capacity For NFκB Activation is Associated With Blunted eIF2α Dephosphorylation In Response To Amino Acids (AA) in Old People
Author(s) -
Wilkes Emilie Anne,
Atherton Philip J,
Selby Anna L,
Smith Ken,
Rennie Michael J,
Cuthbertson Dan J,
Keller Pernille,
Pedersen Bente Klarlund
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a556-a
Subject(s) - anabolism , dephosphorylation , endocrinology , medicine , phosphorylation , basal (medicine) , tumor necrosis factor alpha , chemistry , biology , phosphatase , insulin , biochemistry
Older adults show anabolic blunting of muscle protein synthesis (MPS) with increased AA availability, a phenomenon apparently independent of plasma insulin concentration. This reduced anabolic response includes diminished sensitivity and capacity of the mTOR signalling pathway. In one group of subjects we discovered that when compared to the young, old subjects showed higher muscle NFκB protein (4‐fold), and increase mRNA for TNFα and IL‐6, accompanied by significantly higher plasma TNFα and IL‐6 (2.49 v 1.24 pg/ml and 2.5 v 0.93 pg/ml, respectively). In a separate group, we examined the effect of intravenous AA during a euglycaemic hyperinsulinaemic clamp (141 μ IU/ml) in healthy young (24 y) and elderly (67 y) subjects upon phosphorylation of eIF2α, an mTOR independent protein which was hypothesised to be important in AA‐induced MPS. Phosphorylation of eIF2α fell significantly with feeding only in the young (−49 % v −67 % in the elderly). Associated with this, TNFα precursor protein concentration was higher in the elderly (5.2‐fold) and this was accompanied by enhanced basal IκBα phosphorylation (2.3‐fold) (both P<0.05). These data suggest a potential for heightened NFκB activation in the elderly associated with a blunting of AA‐induced eIF2α dephosphorylation which could be functionally related to the observed anabolic resistance. Supported by The Wellcome Trust, MRC and BBSRC