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 and amino acids exert anabolic actions that arise in part from their ability to phosphorylate ribosomal p70 S6-kinase (p70(S6k)) 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 microg. kg(-1). day(-1), n = 10) or saline (n = 10) for 5 days. We then measured the phosphorylation of PHAS-I and p70(S6k) in rectus muscle biopsies taken before and at the end of a 180-min infusion of either insulin (10 mU. min(-1). kg(-1) 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 p70(S6k) phosphorylation but blocked insulin-stimulated phosphorylation of PHAS-I- and amino acid-stimulated phosphorylation of both PHAS-I and p70(S6k) (P < 0.01, for each). DEX also increased muscle PHAS-I concentration. These effects can, in part, explain glucocorticoid-induced muscle wasting.
Department of Internal Medicine, University of Virginia Health Sciences Center, Charlottesville, VA 22908, USA.
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Barrett
D000596:Amino Acids / Q000494:pharmacology; D000818:Animals; D002352:Carrier Proteins; D003907:Dexamethasone / Q000494:pharmacology*; D005938:Glucocorticoids / Q000494:pharmacology*; D007328:Insulin / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D009124:Muscle Proteins / Q000096:biosynthesis*; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism*
D000596:Amino Acids; D002352:Carrier Proteins; C499526:Eif4ebp1 protein, rat; D005938:Glucocorticoids; D007328:Insulin; D047908:Intracellular Signaling Peptides and Proteins; D009124:Muscle Proteins; D010750:Phosphoproteins; D003907:Dexamethasone; D019893:Ribosomal Protein S6 Kinases