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Departments of Medicine, Pathology and Immunology, Cell Biology and Physiology, and the Center for Cardiovascular Research, Washington University School of Medicine, St. Louis, Missouri 63110
Amino acids and insulin have anabolic effects in skeletal muscle, but the mechanisms are poorly understood. To test the hypothesis that leucine and insulin stimulate translation initiation in human skeletal muscle by phosphorylating 70-kDa ribosomal protein S6 kinase (p70S6k), we infused healthy adults with leucine alone (n = 6), insulin alone (n = 6), or both leucine and insulin (n = 6) for 2 h. p70S6k and protein kinase B (PKB) serine473 phosphorylation were measured in vastus lateralis muscles. Plasma leucine increased from ~116 to 343 µmol/l during the leucine-alone and leucine + insulin infusions. Plasma insulin increased to ~400 pmol/l during the insulin-alone and leucine + insulin infusions and was unchanged during the leucine-alone infusion. Phosphorylation of p70S6k increased 4-fold in response to leucine alone, 8-fold in response to insulin alone, and 18-fold after the leucine + insulin infusion. Insulin-alone and leucine + insulin infusions increased PKB phosphorylation, but leucine alone had no effect. These results show that physiological concentrations of leucine and insulin activate a key mediator of protein synthesis in human skeletal muscle. They suggest that leucine stimulates protein synthesis through a nutrient signaling mechanism independent of insulin, raising the possibility that administration of branched-chain amino acids may improve protein synthesis in insulin-resistant states.
protein synthesis; translation initiation; hyperinsulinemia; mammalian target of rapamycin; insulin resistance
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