Glucocorticoids modulate amino acid-induced translation initiation in human skeletal muscle.
Glucocorticoids modulate amino acid-induced translation initiation in human skeletal muscle.
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DOI：
10.1152/ajpendo.00457.2003
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发表时间：
2004-08
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影响因子：
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通讯作者：
Zhenqi Liu;Guoliang Li;S. Kimball;L. Jahn;E. Barrett
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文献类型：
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作者：
Zhenqi Liu;Guoliang Li;S. Kimball;L. Jahn;E. Barrett
氨基酸是独特的合成代谢剂，因为它们营养地向mRNA翻译起始发出信号，并作为骨骼肌蛋白质合成的底物。糖皮质激素过量对抗氨基酸对实验动物蛋白质合成的合成代谢作用。为了研究过量糖皮质激素是否调节人骨骼肌混合氨基酸信号的翻译起始，我们系统地给16名年轻健康男性志愿者系统地注入了氨基酸混合物(10%曲瓦索)，在没有糖皮质激素过量的情况下(n=8)或在存在糖皮质激素过量的情况下(地塞米松每6 h口服2 mg，连续3天)，持续6 h。注射氨基酸前后取股外侧肌组织，检测真核细胞起始因子(EIF)4E结合蛋白1(4E-BP1)、核糖体蛋白S6K(p70(S6K))和eIF2α的磷酸化及eIF2B的鸟核苷酸交换活性。系统输注混合氨基酸显著刺激对照组4E-BP10.04和p70(S6K)的磷酸化(P<；0.001)和eIF2α的去磷酸化(P<；0.003)。地塞米松处理不改变4E-BP1、p70(S6K)或eIF2α的基础磷酸化状态，但取消了氨基酸输注对4E-BP1磷酸化的刺激作用(P=0.31)，不影响氨基酸诱导的p70(S6K)的磷酸化(P=0.002)或eIF2α的去磷酸化(P=0.003)。氨基酸和地塞米松处理均不改变eIF2B的鸟核苷酸交换活性。结论：在人体骨骼肌中，生理范围内氨基酸浓度的变化通过增强mRNA与43S起始前复合体的结合来刺激mRNA的翻译，而p70(S6K)的活性和糖皮质激素的过量在体内阻止了前者的作用。
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.