Miquet Johanna G, Muñoz Marina C, Giani Jorge F, González Lorena, Dominici Fernando P, Bartke Andrzej, Turyn Daniel, Sotelo Ana I
Instituto de Química y Fisicoquímica Biológicas (UBA-CONICET), Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Junín 956, 1113 Caba, Argentina.
Growth Horm IGF Res. 2010 Apr;20(2):118-26. doi: 10.1016/j.ghir.2009.11.003. Epub 2009 Dec 21.
Growth hormone (GH) is an anabolic hormone that regulates growth and metabolism. Ames dwarf mice are natural mutants for Prop1, with impaired development of anterior pituitary and undetectable levels of circulating GH, prolactin and TSH. They constitute an endocrine model of life-long GH-deficiency. The main signaling cascades activated by GH binding to its receptor are the JAK2/STATs, PI-3K/Akt and the MAPK Erk1/2 pathways.
We have previously reported that GH-induced STAT5 activation was higher in Ames dwarf mice liver compared to non-dwarf controls. The aim of this study was to evaluate the principal components of the main GH-signaling pathways under GH-deficiency in liver and skeletal muscle, another GH-target tissue.
Ames dwarf mice and their non-dwarf siblings were assessed. Animals were injected i.p. with GH or saline 15min before tissue removal. Protein content and phosphorylation of signaling mediators were determined by immunoblotting of tissue solubilizates.
GH was able to induce STAT5 and STAT3 tyrosine phosphorylation in both liver and muscle, but the response was higher for Ames dwarf mice than for non-dwarf controls. When Erk1/2 activation was assessed in liver, only dwarf mice showed GH-induced phosphorylation, while in muscle no response to the hormone was found in either genotype. GH-induced Akt phosphorylation at Ser473 in liver was only detected in dwarf mice. In skeletal muscle, both normal and dwarf mice responded to a GH stimulus, although dwarf mice presented higher GH activation levels. The phosphorylation of GSK-3, a substrate of Akt, increased upon hormone stimulation only in dwarf mice in both tissues. In contrast, no differences in the phosphorylation of mTOR, another substrate of Akt, were observed after GH stimulus, either in normal or dwarf mice in liver, while we were unable to determine mTOR in muscle. Protein content of GH-receptor and of the signaling mediators studied did not vary between normal and dwarf animals in the assessed tissues.
These results show that several components of the main GH-signaling pathways exhibit enhanced sensitivity to the hormone in liver and muscle of Ames dwarf mice.
生长激素（GH）是一种调节生长和代谢的合成代谢激素。艾姆斯侏儒小鼠是Prop1的天然突变体，垂体前叶发育受损，循环中的生长激素、催乳素和促甲状腺激素水平检测不到。它们构成了终身生长激素缺乏的内分泌模型。生长激素与其受体结合后激活的主要信号级联是JAK2/STATs、PI-3K/Akt和MAPK Erk1/2途径。
我们之前报道过，与非侏儒对照相比，艾姆斯侏儒小鼠肝脏中生长激素诱导的STAT5激活更高。本研究的目的是评估肝脏和骨骼肌（另一个生长激素靶组织）在生长激素缺乏情况下主要生长激素信号通路的主要成分。
对艾姆斯侏儒小鼠及其非侏儒同胞进行评估。在取出组织前15分钟，给动物腹腔注射生长激素或生理盐水。通过对组织溶解产物进行免疫印迹来测定信号介质的蛋白质含量和磷酸化情况。
生长激素能够在肝脏和肌肉中诱导STAT5和STAT3酪氨酸磷酸化，但艾姆斯侏儒小鼠的反应比非侏儒对照更高。在肝脏中评估Erk1/2激活时，只有侏儒小鼠表现出生长激素诱导的磷酸化，而在肌肉中，两种基因型对该激素均无反应。生长激素诱导的肝脏中Ser473位点的Akt磷酸化仅在侏儒小鼠中检测到。在骨骼肌中，正常和侏儒小鼠均对生长激素刺激有反应，尽管侏儒小鼠的生长激素激活水平更高。Akt的底物GSK-3的磷酸化仅在两种组织的侏儒小鼠中受到激素刺激后增加。相比之下，在肝脏中，无论是正常还是侏儒小鼠，生长激素刺激后，另一个Akt底物mTOR的磷酸化均未观察到差异，而我们无法在肌肉中测定mTOR。在所评估的组织中，正常和侏儒动物之间生长激素受体和所研究的信号介质的蛋白质含量没有差异。
这些结果表明，主要生长激素信号通路的几个成分在艾姆斯侏儒小鼠的肝脏和肌肉中对该激素表现出更高的敏感性。
Zotero 插件