Muscle-specific inactivation of the IGF-I receptor induces compensatory hyperplasia in skeletal muscle
Muscle-specific inactivation of the IGF-I receptor induces compensatory hyperplasia in skeletal muscle
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DOI：
10.1172/jci200213503
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发表时间：
2002-02-01
影响因子：
15.9
通讯作者：
Le Roith, D
中科院分区：
文献类型：
--
作者：
Fernández, AM;Dupont, J;Le Roith, D
在骨骼肌的发育过程中，成肌细胞退出细胞周期并分化成肌管。已知胰岛素样生长因子IGF-I和IGF-II通过其同源酪氨酸激酶受体（IGF-I受体）在该过程中发挥作用。成肌细胞退出细胞周期后，IGF-I通过诱导生肌调节因子（MyoD、肌生成素）和效应因子（p21）的表达或活性来促进肌肉分化。然而，很少有人知道的细胞内的机制，IGF-I系统调节这些因素在肌发生的过程中。在这里，我们表明，MKR小鼠，表达显性负IGF-I受体特异性骨骼肌，有显着的肌肉发育不全，从出生到3周龄。这种发育不全伴随ERK免疫反应性水平降低和MyoD和肌细胞生成素表达降低。BrdU免疫细胞化学显示MKR小鼠生长至成年时出现代偿性增生。有趣的是，增生伴随着p38、MyoD、肌细胞生成素和p21免疫反应性水平的增加以及Twist水平的降低而发生。这些结果表明，IGF-I对这些细胞成分的调节可能在体内骨骼肌的发育和分化中发挥作用。
During the development of skeletal muscle, myoblasts withdraw from the cell cycle and differentiate into myotubes. The insulin-like growth factors IGF-I and IGF-II, through their cognate tyrosine kinase receptor (IGF-I receptor), are known to play a role in this process. After withdrawal of myoblasts from the cell cycle, IGF-I promotes muscle differentiation by inducing the expression or activity of myogenic regulatory factors (MyoD, myogenin) and effectors (p21). However, little is known about the intracellular mechanisms by which the IGF-I system regulates these factors during the process of myogenesis. Here we show that MKR mice, which express a dominant negative IGF-I receptor specifically in skeletal muscle, have marked muscle hypoplasia from birth to 3 weeks of age. This hypoplasia occurs concomitantly with a decrease in ERK immunoreactivity levels and decreases in MyoD and myogenin expression. BrdU immunocytochemistry showed a compensatory hyperplasia as MKR mice grew to adulthood. Interestingly, hyperplasia occurred concomitantly with an increase in p38, MyoD, myogenin, and p21 immunoreactivity levels, as well as a decrease in Twist levels. These findings suggest that regulation of these cellular elements by IGF-I may play a role in the development and differentiation of skeletal muscle in vivo.