Glucocorticoids modulate amino acid-induced translation initiation in human skeletal muscle.
Amino acids are unique anabolic agents in that they nutritively signal to mRNA translation initiation and serve as substrates for protein synthesis in skeletal muscle. Glucocorticoid excess antagonizes the anabolic action of amino acids on protein synthesis in laboratory animals. To examine whether excessive glucocorticoids modulate mixed amino acid-signaled translation initiation in human skeletal muscle, we infused an amino acid mixture (10% Travasol) systemically to 16 young healthy male volunteers for 6 h in the absence (n = 8) or presence (n = 8) of glucocorticoid excess (dexamethasone 2 mg orally every 6 h for 3 days). Vastus lateralis muscles were biopsied before and after amino acid infusion, and the phosphorylation of eukaryotic initiation factor (eIF) 4E-binding protein 1 (4E-BP1), ribosomal protein S6 kinase (p70(S6K)), and eIF2alpha and the guanine nucleotide exchange activity of eIF2B were measured. Systemic infusion of mixed amino acids significantly stimulated the phosphorylation of 4E-BP1 (P < 0.04) and p70(S6K) (P < 0.001) and the dephosphorylation of eIF2alpha (P < 0.003) in the control group. Dexamethasone treatment did not alter the basal phosphorylation state of 4E-BP1, p70(S6K), or eIF2alpha; however, it abrogated the stimulatory effect of amino acid infusion on the phosphorylation of 4E-BP1 (P = 0.31) without affecting amino acid-induced phosphorylation of p70(S6K) (P = 0.002) or dephosphorylation of eIF2alpha (P = 0.003). Neither amino acid nor dexamethasone treatment altered the guanine nucleotide exchange activity of eIF2B. We conclude that changes of amino acid concentrations within the physiological range stimulate mRNA translation by enhancing the binding of mRNA to the 43S preinitiation complex, and the activity of p70(S6K) and glucocorticoid excess blocks the former action in vivo in human skeletal muscle.
Liu
Zhenqi
Z
Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Virginia Health System, Charlottesville, VA 22908-1410, USA. zl3e@virginia.edu
Li
Guolian
G
Kimball
Scot R
SR
Jahn
Linda A
LA
Barrett
Eugene J
EJ
D048868:Adaptor Proteins, Signal Transducing; D000284:Administration, Oral; D000328:Adult; D000596:Amino Acids / Q000378:metabolism*; D001786:Blood Glucose / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D018797:Cell Cycle Proteins; D003907:Dexamethasone / Q000008:administration & dosage* / Q000378:metabolism; D004334:Drug Administration Schedule; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D020717:Eukaryotic Initiation Factor-2B / Q000378:metabolism; D005938:Glucocorticoids / Q000008:administration & dosage* / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000097:blood; D008297:Male; D009124:Muscle Proteins / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D014176:Protein Biosynthesis / Q000502:physiology*; D012016:Reference Values; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D000596:Amino Acids; D001786:Blood Glucose; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; D015852:Eukaryotic Initiation Factor-2; D020717:Eukaryotic Initiation Factor-2B; D005938:Glucocorticoids; D007328:Insulin; D009124:Muscle Proteins; D010750:Phosphoproteins; D003907:Dexamethasone; D038762:Ribosomal Protein S6 Kinases, 70-kDa