TACE release of TNF-α mediates mechanotransduction-induced activation of p38 MAPK and myogenesis
TACE release of TNF-α mediates mechanotransduction-induced activation of p38 MAPK and myogenesis
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DOI：
10.1242/jcs.03372
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发表时间：
2007-02-15
影响因子：
4
通讯作者：
Li, Yi-Ping
中科院分区：
文献类型：
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作者：
Zhan, Mei;Jin, Bingwen;Li, Yi-Ping
骨骼肌通过激活p38 MAPK来响应机械刺激，p38 MAPK是肌肉形成的关键信号。然而，激活p38的机械转导机制尚不清楚。在这里，我们发现机械刺激成肌细胞通过刺激tnf - α转换酶（TACE）释放tnf - α来激活p38和肌肉发生。在生长培养基中培养的C2C12或小鼠原代成肌细胞中，静态拉伸激活了p38以及ERK1/2、JNK和AKT。通过tnf - α中和抗体破坏tnf - α信号传导或敲除tnf - α受体可阻断p38的拉伸激活，但对ERK1/2、JNK或AKT无效。Stretch还以依赖tnf - α和p38的方式激活分化标记物MEF2C、肌原蛋白、p21和肌球蛋白重链。拉伸刺激TACE的裂解活性。相反，TACE抑制剂TAPI或TACE siRNA可消除p38的拉伸激活。此外，拉伸成肌细胞培养的条件培养基激活了未拉伸成肌细胞中的p38，这需要供体成肌细胞中的TACE活性和受体成肌细胞中的tnf - α受体活性。这些结果表明，TACE的转录后激活介导了通过释放tnf - α激活p38依赖性肌生成的机械转导。
Skeletal muscle responds to mechanical stimulation by activating p38 MAPK, a key signal for myogenesis. However, the mechanotransduction mechanism that activates p38 is unknown. Here we show that mechanical stimulation of myoblasts activates p38 and myogenesis through stimulating TNF-alpha release by TNF-alpha converting enzyme (TACE). In C2C12 or mouse primary myoblasts cultured in growth medium, static stretch activated p38 along with ERK1/2, JNK and AKT. Disrupting TNF-alpha signaling by TNF-alpha-neutralizing antibody or knocking out TNF-alpha receptors blocked stretch activation of p38, but not ERK1/2, JNK or AKT. Stretch also activated differentiation markers MEF2C, myogenin, p21 and myosin heavy chain in a TNF-alpha- and p38-dependent manner. Stretch stimulated the cleavage activity of TACE. Conversely, TACE inhibitor TAPI or TACE siRNA abolished stretch activation of p38. In addition, conditioned medium from stretched myoblast cultures activated p38 in unstretched myoblasts, which required TACE activity in the donor myoblasts, and TNF-alpha receptors in the recipient myoblasts. These results indicate that posttranscriptional activation of TACE mediates the mechanotransduction that activates p38-dependent myogenesis via the release of TNF-alpha.