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首页> 外文期刊>American Journal of Physiology >High concentrations of HGF inhibit skeletal muscle satellite cell proliferation in vitro by inducing expression of myostatin: a possible mechanism for reestablishing satellite cell quiescence in vivo.
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High concentrations of HGF inhibit skeletal muscle satellite cell proliferation in vitro by inducing expression of myostatin: a possible mechanism for reestablishing satellite cell quiescence in vivo.

机译：高浓度的HGF通过诱导肌生长抑制素的表达在体外抑制骨骼肌卫星细胞的增殖：这是体内重建卫星细胞静止的一种可能的机制。

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摘要

Skeletal muscle regeneration and work-induced hypertrophy rely on molecular events responsible for activation and quiescence of resident myogenic stem cells, satellite cells. Recent studies demonstrated that hepatocyte growth factor (HGF) triggers activation and entry into the cell cycle in response to mechanical perturbation, and that subsequent expression of myostatin may signal a return to cell quiescence. However, mechanisms responsible for coordinating expression of myostatin after an appropriate time lag following activation and proliferation are not clear. Here we address the possible role of HGF in quiescence through its concentration-dependent negative-feedback mechanism following satellite cell activation and proliferation. When activated/proliferating satellite cell cultures were treated for 24 h beginning 48-h postplating with 10-500 ng/ml HGF, the percentage of bromodeoxyuridine-incorporating cells decreased down to a baseline level comparable to 24-h control cultures in a HGF dose-dependent manner. The high level HGF treatment did not impair the cell viability and differentiation levels, and cells could be reactivated by lowering HGF concentrations to 2.5 ng/ml, a concentration that has been shown to optimally stimulate activation of satellite cells in culture. Coaddition of antimyostatin neutralizing antibody could prevent deactivation and abolish upregulation of cyclin-dependent kinase (Cdk) inhibitor p21. Myostatin mRNA expression was upregulated with high concentrations of HGF, as demonstrated by RT-PCR, and enhanced myostatin protein expression and secretion were revealed by Western blots of the cell lysates and conditioned media. These results indicate that HGF could induce satellite cell quiescence by stimulating myostatin expression. The HGF concentration required (over 10-50 ng/ml), however, is much higher than that for activation, which is initiated by rapid release of HGF from its extracellular association. Considering that HGF is produced by satellite cells and spleen and liver cells in response to muscle damage, local concentrations of HGF bathing satellite cells may reach a threshold sufficient to induce myostatin expression. This time lag may delay action of the quiescence signaling program in proliferating satellite cells during initial phases of muscle regeneration followed by induction of quiescence in a subset of cells during later phases.
机译：骨骼肌的再生和工作诱导的肥大依赖于分子事件，该分子事件负责驻留的成肌干细胞，卫星细胞的活化和静止。最近的研究表明，肝细胞生长因子（HGF）响应机械扰动而触发激活和进入细胞周期，并且肌生长抑制素的后续表达可能表示细胞恢复静止。然而，激活和增殖后一段适当的时间间隔后，负责协调肌生长抑制素表达的机制尚不清楚。在这里，我们通过卫星细胞激活和增殖后其浓度依赖性负反馈机制解决HGF在静止状态中的可能作用。当在接种后48-h开始用10-500 ng / ml HGF对活化/增殖的卫星细胞培养物进行24小时处理时，掺入溴脱氧尿苷的细胞的百分比降低到基线水平，与HGF剂量的24小时对照培养物相当依赖的方式。高水平的HGF处理不会损害细胞活力和分化水平，并且可以通过将HGF浓度降低至2.5 ng / ml来重新激活细胞，该浓度已被证明可以最佳地刺激培养物中卫星细胞的激活。抗肌生成抑制素中和抗体的共添加可以防止失活并消除细胞周期蛋白依赖性激酶（Cdk）抑制剂p21的上调。如RT-PCR所示，高浓度的HGF抑制了肌生长抑制素mRNA的表达，细胞裂解物和条件培养基的蛋白质印迹显示肌生长抑制素蛋白的表达和分泌增强。这些结果表明HGF可以通过刺激肌生长抑制素表达来诱导卫星细胞静止。但是，所需的HGF浓度（超过10-50 ng / ml）远远高于激活所需的浓度，这是由HGF从其细胞外缔合中快速释放所引起的。考虑到HGF是由卫星细胞以及脾和肝细胞响应肌肉损伤而产生的，因此沐浴卫星细胞的HGF局部浓度可能达到足以诱导肌生长抑制素表达的阈值。该时间滞后可能会延迟肌肉再生初始阶段在增殖卫星细胞中的静止信号传导程序的作用，随后在随后的阶段中诱导细胞子集的静止。

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