Dexamethasone inhibits the stimulation of muscle protein synthesis and PHAS-I and p70 S6-kinase phosphorylation

Glucocorticoids inhibit protein synthesis in muscle. In contrast, insulin a nd amino acids exert anabolic actions that arise in part from their ability to phosphorylate ribosomal p70 S6-kinase (p70(S6k)) and eukaryotic initiat ion factor (eIF)4E binding protein (BP)1 (PHAS-I), proteins that regulate t ranslation initiation. Whether glucocorticoids interfere with this action w as examined by giving rats either dexamethasone (DEX, 300 mug.kg(-1).day(-1 ), n = 10) or saline (n = 10) for 5 days. We then measured the phosphorylat ion of PHAS-I and p70(S6k) in rectus muscle biopsies taken before and at th e end of a 180-min infusion of either insulin (10 mU.min(-1).kg(-1) euglyce mic insulin clamp, n 5 5 for both DEX- and saline-treated groups) or a bala nced amino acid mixture (n 5 5 for each group also). Protein synthesis was also measured during the infusion period. The results were that DEX- treate d rats had higher fasting insulin, slower glucose disposal, less lean body mass, and decreased protein synthetic rates during insulin or amino acid in fusion (P < 0.05 each). DEX did not affect basal PHAS-I or p70(S6k) phospho rylation but blocked insulin-stimulated phosphorylation of PHAS-I- and amin o acid-stimulated phosphorylation of both PHAS-I and p70(S6k) (P < 0.01, fo r each). DEX also increased muscle PHAS-I concentration. These effects can, in part, explain glucocorticoid-induced muscle wasting.