Glucocorticoids modulate amino acid-induced translation initiation in human skeletal muscle

Zhenqi Liu, Guolian Li, Scot Kimball, Linda A. Jahn, Eugene J. Barrett

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

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 (p70S6K), and eIF2α 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 eIF2α (P < 0.003) in the control group. Dexamethasone treatment did not alter the basal phosphorylation state of 4E-BP1, p70S6K, or eIF2α; 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 eIF2α (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 p70S6K and glucocorticoid excess blocks the former action in vivo in human skeletal muscle.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Volume287
Issue number2 50-2
DOIs
StatePublished - Aug 1 2004

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Glucocorticoids
Skeletal Muscle
70-kDa Ribosomal Protein S6 Kinases
Amino Acids
Phosphorylation
Carrier Proteins
Dexamethasone
Guanine Nucleotides
Protein Biosynthesis
Eukaryotic Initiation Factor-4E
Ribosomal Protein S6 Kinases
Anabolic Agents
Quadriceps Muscle
Laboratory Animals
Healthy Volunteers
Proteins
Muscles
Control Groups
Messenger RNA
Therapeutics

All Science Journal Classification (ASJC) codes

  • Endocrinology, Diabetes and Metabolism
  • Physiology
  • Physiology (medical)

Cite this

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title = "Glucocorticoids modulate amino acid-induced translation initiation in human skeletal muscle",
abstract = "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 (p70S6K), and eIF2α 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 eIF2α (P < 0.003) in the control group. Dexamethasone treatment did not alter the basal phosphorylation state of 4E-BP1, p70S6K, or eIF2α; 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 eIF2α (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 p70S6K and glucocorticoid excess blocks the former action in vivo in human skeletal muscle.",
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Glucocorticoids modulate amino acid-induced translation initiation in human skeletal muscle. / Liu, Zhenqi; Li, Guolian; Kimball, Scot; Jahn, Linda A.; Barrett, Eugene J.

In: American Journal of Physiology - Endocrinology and Metabolism, Vol. 287, No. 2 50-2, 01.08.2004.

Research output: Contribution to journalArticle

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