Xu X, Bennett S A, Ingram R L, Sonntag W E
Department of Physiology and Pharmacology, Bowman Gray School of Medicine of Wake Forest University, Winston-Salem, North Carolina 27157-1083, USA.
Endocrinology. 1995 Oct;136(10):4551-7. doi: 10.1210/endo.136.10.7664676.
Several investigations have clearly indicated that plasma concentrations of insulin-like growth factor I (IGF-I) decrease with age and contribute to the decrease in tissue function that is characteristic of aging animals and man. Plasma IGF-I is regulated by GH released from the pituitary gland, and although data demonstrate a decline in GH secretion with age, GH receptor (GHR) density in liver tissue has been reported to increase. In this study, the effects of aging on GHR signal transduction were assessed in hepatic tissue to determine whether alterations in the response to GH contribute to the decline in IGF-I. Liver slices from female C57BL/6 mice (10, 17, and 31 months old) were prepared in medium and stimulated with GH. Basal GHR binding increased more than 2-fold in 31-month-old animals compared to that in either 10- or 17-month-old animals (P < 0.01), whereas the Ka values were similar in the three age groups. However, GH (2 nM)-induced IGF-I gene expression decreased dramatically with age (P < 0.01). In 10-month-old animals, GH-induced phosphorylation of the GHR complex was maximal 10 min after the addition of hormone, whereas GH-induced MAP kinase activity was maximal at 15 min. GH-induced JAK2 kinase and GHR complex phosphorylation as well as MAP kinase activity were significantly lower in 31-month-old animals than in either the 10- or 17-month-old groups (P < 0.05). The results of this study demonstrate that GH induces phosphorylation of JAK2 and the GHR complex, activates MAP kinase, and increases the expression of IGF-I messenger RNA in liver. In 17-month-old animals, decreases in IGF-I gene expression were evident that were not directly associated with diminished GHR complex phosphorylation or MAP kinase activity. By 31 months, there was a decrease in IGF-I gene expression that was associated with a marked decline in JAK2 and GHR complex phosphorylation. These data suggest that the signal transduction pathway for GH is impaired with age and that these changes may contribute to the decline in IGF-I gene expression.
多项研究已明确表明，胰岛素样生长因子I（IGF-I）的血浆浓度会随着年龄增长而降低，这与衰老动物和人类所特有的组织功能衰退有关。血浆IGF-I受垂体释放的生长激素（GH）调节，尽管数据显示GH分泌会随着年龄增长而下降，但据报道肝脏组织中的生长激素受体（GHR）密度会增加。在本研究中，评估了衰老对肝脏组织中GHR信号转导的影响，以确定对GH反应的改变是否导致了IGF-I的下降。将雌性C57BL/6小鼠（10、17和31月龄）的肝脏切片置于培养基中并用GH刺激。与10月龄或17月龄动物相比，31月龄动物的基础GHR结合增加了两倍多（P < 0.01），而三个年龄组的Ka值相似。然而，GH（2 nM）诱导的IGF-I基因表达随年龄增长而显著下降（P < 0.01）。在10月龄动物中，添加激素后10分钟时GH诱导的GHR复合物磷酸化达到最大值，而GH诱导的丝裂原活化蛋白激酶（MAP激酶）活性在15分钟时达到最大值。31月龄动物中GH诱导的JAK2激酶和GHR复合物磷酸化以及MAP激酶活性显著低于10月龄或17月龄组（P < 0.05）。本研究结果表明，GH诱导JAK2和GHR复合物磷酸化，激活MAP激酶，并增加肝脏中IGF-I信使核糖核酸的表达。在17月龄动物中，IGF-I基因表达明显下降，这与GHR复合物磷酸化或MAP激酶活性的降低没有直接关联。到31月龄时，IGF-I基因表达下降，这与JAK2和GHR复合物磷酸化的显著下降有关。这些数据表明，GH的信号转导途径会随着年龄增长而受损，这些变化可能导致IGF-I基因表达下降。
