Hypoxia converts the myogenic action of insulin-like growth factors into mitogenic action by differentially regulating multiple signaling pathways
Hypoxia converts the myogenic action of insulin-like growth factors into mitogenic action by differentially regulating multiple signaling pathways
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DOI：
10.1073/pnas.0909570107
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发表时间：
2010-03-30
影响因子：
11.1
通讯作者：
Duan, Cunming
中科院分区：
文献类型：
--
作者：
Ren, Hongxia;Accili, Domenico;Duan, Cunming
胰岛素样生长因子(IGF)刺激成肌细胞的增殖和分化。这些相互排斥的细胞反应是如何由相同的生长因子引发的，目前仍然难以捉摸。在此，我们报道了IGF在常氧条件下促进成肌细胞分化，在低氧条件下刺激增殖。低氧激活HIF-1转录程序，而HIF-1α的敲除将IGF在低氧条件下的促有丝分裂作用转变为促肌作用。相反，HIF-1α的过度表达取消了IGF在常氧条件下的生肌作用。在常氧条件下，IGF激活Akt-mTOR、p38和ERK1/2 MAPK通路。低氧抑制基础和IGF诱导的Akt-mTOR和p38活性，而以HIF-1依赖的方式增强和延长IGF诱导的ERK1/2激活。Akt-mTOR和p38的激活促进了肌肉的生成，p38也抑制了细胞的增殖。ERK的激活促进成肌细胞的增殖，但抑制其分化。这些结果表明，低氧通过HIF-1依赖的机制对多条信号通路进行差异性调控，从而将IGFS的生肌作用转化为促有丝分裂作用。我们的发现为IGFS在肌肉发生过程中的矛盾行为提供了一种机制解释，并揭示了一种新的机制，即细胞感知和整合生长因子信号和微环境中的氧气供应。
Insulin-like growth factors (IGFs) stimulate myoblast proliferation and differentiation. It remains elusive how these mutually exclusive cellular responses are elicited by the same growth factor. Here we report that whereas IGF promotes myoblast differentiation under normoxia, it stimulates proliferation under hypoxia. Hypoxia activates the HIF-1 transcriptional program and knockdown of HIF-1 alpha changes the mitogenic action of IGF into myogenic action under hypoxia. Conversely, overexpression of HIF-1 alpha abolishes the myogenic effect of IGF under normoxia. Under normoxia, IGF activates the Akt-mTOR, p38, and Erk1/2 MAPK pathways. Hypoxia suppresses basal and IGF-induced Akt-mTOR and p38 activity, whereas it enhances and prolongs IGF-induced Erk1/2 activation in a HIF-1-dependent fashion. Activation of Akt-mTOR and p38 promotes myogenesis, and p38 also inhibits proliferation. Activation of Erk stimulates myoblast proliferation but inhibits differentiation. These results suggest that hypoxia converts the myogenic action of IGFs into mitogenic action by differentially regulating multiple signaling pathways via HIF-1-dependent mechanisms. Our findings provide a mechanistic explanation for the paradoxical actions of IGFs during myogenesis and reveal a novel mechanism by which cells sense and integrate growth factor signals and oxygen availability in their microenvironments.