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Am J Physiol Endocrinol Metab (March 23, 2004). doi:10.1152/ajpendo.00457.2003
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Submitted on October 9, 2003
Accepted on March 14, 2004

Glucocorticoids Modulate Amino Acid-induced Translation Initiation by Abrogating 4E-BP1 Phosphorylation in Human Skeletal Muscle

Zhenqi Liu1*, Guolian Li1, Scot R. Kimball2, Linda A. Jahn1, and Eugene J. Barrett1

1 Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Virginia Health System, Charlottesville, VA, USA
2 Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, PA, USA

* To whom correspondence should be addressed. E-mail: zl3e{at}virginia.edu.

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 acids-signaled translation initiation in human skeletal muscle, we infused an amino acid mixture (10% Travasol®) systemically to 16 young healthy male volunteers for 6 hours in the absence (n=8) or presence (n=8) of glucocorticoid excess (dexamethasone 2 mg orally every 6 hours 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 (p70S6K) and eIF2{alpha} 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 p70S6K (p<0.001) and the dephosphorylation of eIF2{alpha} (p<0.003) in the control group. Dexamethasone treatment did not alter the basal phosphorylation state of either 4E-BP1, p70S6K or eIF2{alpha}, 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 p70S6K (p=0.002) or dephosphorylation of eIF2{alpha} (p=0.003). Neither amino acids 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 pre-initiation complex and the activity of p70S6K and glucocorticoid excess blocks the former action in vivo in human skeletal muscle.




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