Distinct growth hormone receptor signaling modes regulate skeletal muscle development and insulin sensitivity in mice
Distinct growth hormone receptor signaling modes regulate skeletal muscle development and insulin sensitivity in mice
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DOI：
10.1172/jci42447
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发表时间：
2010-11-01
影响因子：
15.9
通讯作者：
Clemens, Thomas L.
中科院分区：
文献类型：
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作者：
Mavalli, Mahendra D.;DiGirolamo, Douglas J.;Clemens, Thomas L.
骨骼肌发育、营养吸收和营养利用在很大程度上由生长激素 (GH) 及其下游效应因子（特别是 IGF-1）协调。然而，尚不清楚 GH 对骨骼肌的哪些作用是直接的，哪些是 GH 诱导的 IGF-1 表达的继发作用。因此，我们培育了骨骼肌中缺乏 GH 受体 (GHR) 或 IGF-1 受体 (IGF-1R) 的小鼠。两者都表现出骨骼肌发育受损，其特征是肌纤维数量和面积减少以及伴随的功能表现缺陷。 GHR 和 IGF-1R 突变体中的骨骼肌发育缺陷可归因于成肌细胞融合减少，并与活化 T 细胞输入和活性的核因子受损有关。引人注目的是，缺乏 GHR 的小鼠出现了 IGF-1R 突变体中未观察到的代谢特征，包括明显的外周肥胖、胰岛素抵抗和葡萄糖耐受不良。 GHR 缺陷肌管中的胰岛素抵抗源自 IR 蛋白丰度降低和 IRS-1 Ser 1101 上的抑制性磷酸化增加。这些结果确定了 GHR 调节骨骼肌发育和调节营养代谢的不同信号传导途径。
Skeletal muscle development, nutrient uptake, and nutrient utilization is largely coordinated by growth hormone (GH) and its downstream effectors, in particular, IGF-1. However, it is not clear which effects of GH on skeletal muscle are direct and which are secondary to GH-induced IGF-1 expression. Thus, we generated mice lacking either GH receptor (GHR) or IGF-1 receptor (IGF-1R) specifically in skeletal muscle. Both exhibited impaired skeletal muscle development characterized by reductions in myofiber number and area as well as accompanying deficiencies in functional performance. Defective skeletal muscle development, in both GHR and IGF-1R mutants, was attributable to diminished myoblast fusion and associated with compromised nuclear factor of activated T cells import and activity. Strikingly, mice lacking GHR developed metabolic features that were not observed in the IGF-1R mutants, including marked peripheral adiposity, insulin resistance, and glucose intolerance. Insulin resistance in GHR-deficient myotubes derived from reduced IR protein abundance and increased inhibitory phosphorylation of IRS-1 on Ser 1101. These results identify distinct signaling pathways through which GHR regulates skeletal muscle development and modulates nutrient metabolism.