TNF-α regulates early differentiation of C2C12 myoblasts in an autocrine fashion
TNF-α regulates early differentiation of C2C12 myoblasts in an autocrine fashion
复制标题
DOI：
10.1096/fj.00-0632fje
复制
发表时间：
2001-04-27
期刊：
影响因子：
4.8
通讯作者：
Schwartz, RJ
中科院分区：
文献类型：
--
作者：
Li, YP;Schwartz, RJ
肿瘤坏死因子-α（TNF-α）作为一种体液因子，长期以来一直被认为是介导骨骼肌蛋白酶的因子。然而，最近的研究发现，肌肉通常合成TNF-α，剧烈运动增加健康个体的循环TNF-α，这一细胞因子也可能在骨骼肌中发挥生理作用。在这项研究中，我们观察到C2 C12成肌细胞中TNF-α表达的基础水平，血清限制显著上调。血清限制也增加了核因子-κ B（NF-κ B）的活性，这可以被TNF-α中和抗体阻断。这种抗体也抑制分化标志物，成人快速肌球蛋白重链的表达，在最初的24小时的血清限制。相反，快速肌球蛋白重链的表达刺激外源性TNF-α在同一时间段内，这可能是由一个显性负抑制剂NF-κ B激活。TNF-α迅速刺激血清反应因子（SRF）的结合活性，SRF是成肌细胞分化所需的转录因子，并刺激SRF依赖性骨骼肌α-肌动蛋白基因的表达。这些结果首次证明，TNT-α是一种内源性肌肉因子，通过刺激NF-κ B和SRF活性促进早期分化。
Tumor necrosis factor-alpha (TNF-alpha) has long been known to mediate skeletal muscle protein catabolism as a humoral factor. However, recent findings that muscle normally synthesizes TNF-alpha and that strenuous exercise increases circulating TNF-alpha in healthy individuals raised the possibility that this cytokine may also have a physiological role in skeletal muscle. In this study, we observed a basal level of TNF-alpha expression in C2C12 myoblasts that was markedly up-regulated by serum restriction. Serum restriction also increased nuclear factor-kappaB (NF-kappaB) activity, which could be blocked by a TNF-alpha-neutralizing antibody. This antibody also inhibited the expression of a differentiation marker, adult fast myosin heavy chain, during the initial 24 h of serum restriction. Conversely, fast myosin heavy chain expression was stimulated by exogenous TNF-alpha during the same time period, which could be blocked by a dominant negative inhibitor of NF-kappaB activation. TNF-alpha rapidly stimulated the binding activity of serum response factor (SRF), a transcription factor required for myoblast differentiation, and expression of the SRF-dependent skeletal muscle alpha-actin gene. These results demonstrate for the first time that TNT-alpha is an endogenous muscle factor that promotes the early phase of differentiation by stimulating NF-kappaB and SRF activity.