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Department of Internal Medicine, University of Virginia Health Sciences Center, Charlottesville, Virginia 22908
Glucocorticoids inhibit protein synthesis in
muscle. In contrast, insulin and amino acids exert anabolic actions
that arise in part from their ability to phosphorylate ribosomal p70
S6-kinase (p70S6k) and eukaryotic initiation factor (eIF)4E
binding protein (BP)1 (PHAS-I), proteins that regulate translation
initiation. Whether glucocorticoids interfere with this action was
examined by giving rats either dexamethasone (DEX, 300 µg · kg
1 · day1,
n = 10) or saline (n = 10) for 5 days.
We then measured the phosphorylation of PHAS-I and p70S6k
in rectus muscle biopsies taken before and at the end of a 180-min infusion of either insulin (10 mU · min1 · kg1 euglycemic
insulin clamp, n = 5 for both DEX- and saline-treated groups) or a balanced amino acid mixture (n = 5 for
each group also). Protein synthesis was also measured during the
infusion period. The results were that DEX-treated rats had higher
fasting insulin, slower glucose disposal, less lean body mass, and
decreased protein synthetic rates during insulin or amino acid infusion (P < 0.05 each). DEX did not affect basal PHAS-I or
p70S6k phosphorylation but blocked insulin-stimulated
phosphorylation of PHAS-I- and amino acid-stimulated phosphorylation of
both PHAS-I and p70S6k (P < 0.01, for
each). DEX also increased muscle PHAS-I concentration. These effects
can, in part, explain glucocorticoid-induced muscle wasting.
glucocorticoid; translation initiation; eukaryotic initiation factor 4E
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