Dept of Anatomy & Embryology and NUTRIM School for Nutrition, Toxicology, and Metabolism, Maastricht University, P.O. Box 616, 6200 MD, Maastricht, The Netherlands.
J Biol Chem. 2011 Mar 18;286(11):8866-74. doi: 10.1074/jbc.M110.216119. Epub 2011 Jan 14.
Suckling "F/A2" mice, which overexpress arginase-I in their enterocytes, develop a syndrome (hypoargininemia, reduced hair and muscle growth, impaired B-cell maturation) that resembles IGF1 deficiency. The syndrome may result from an impaired function of the GH-IGF1 axis, activation of the stress-kinase GCN2, and/or blocking of the mTORC1-signaling pathway. Arginine deficiency inhibited GH secretion and decreased liver Igf1 mRNA and plasma IGF1 concentration, but did not change muscle IGF1 concentration. GH supplementation induced Igf1 mRNA synthesis, but did not restore growth, ruling out direct involvement of the GH-IGF1 axis. In C2C12 muscle cells, arginine withdrawal activated GCN2 signaling, without impacting mTORC1 signaling. In F/A2 mice, the reduction of plasma and tissue arginine concentrations to ∼25% of wild-type values activated GCN2 signaling, but mTORC1-mediated signaling remained unaffected. Gcn2-deficient F/A2 mice suffered from hypoglycemia and died shortly after birth. Because common targets of all stress kinases (eIF2α phosphorylation, Chop mRNA expression) were not increased in these mice, the effects of arginine deficiency were solely mediated by GCN2.
吸吮过表达肠细胞精氨酸酶-I 的“F/A2”小鼠，会发展出一种综合征（低精氨酸血症、毛发和肌肉生长减少、B 细胞成熟受损），类似于 IGF1 缺乏症。该综合征可能是由于 GH-IGF1 轴功能受损、应激激酶 GCN2 激活和/或 mTORC1 信号通路受阻所致。精氨酸缺乏抑制 GH 分泌，并降低肝脏 Igf1 mRNA 和血浆 IGF1 浓度，但不改变肌肉 IGF1 浓度。GH 补充诱导 Igf1 mRNA 合成，但不能恢复生长，排除了 GH-IGF1 轴的直接参与。在 C2C12 肌肉细胞中，精氨酸缺失激活 GCN2 信号通路，而不影响 mTORC1 信号通路。在 F/A2 小鼠中，血浆和组织精氨酸浓度降低至野生型的约 25%，激活 GCN2 信号通路，但 mTORC1 介导的信号通路不受影响。Gcn2 缺陷型 F/A2 小鼠患有低血糖症，并在出生后不久死亡。由于所有应激激酶的共同靶标（eIF2α 磷酸化、Chop mRNA 表达）在这些小鼠中没有增加，因此精氨酸缺乏的影响仅由 GCN2 介导。
