Molecular mechanisms of resident myogenic stem cell activation and quiescence and their possible regulation by functional food ingredients

骨骼肌再生和工作诱导的肥大依赖于驻留的肌源性干细胞和卫星细胞的激活和静止的分子事件。目前对卫星细胞的培养和体内研究表明，肝细胞生长因子（HGF）在一系列激活级联事件中的重要作用，包括钙钙调素复合物的形成、一氧化氮合酶（cNOS-1）的激活、NO自由基的产生、基质金属蛋白酶（MMP）的激活、HGF与相关的细胞外蛋白聚糖片段的释放，以及HGF与高亲和力受体c-met的结合。这些实验还表明，HGF可以通过刺激肌肉生长抑制素的表达诱导卫星细胞静止，但所需的HGF浓度（超过10-50 ng/ml）远高于激活所需的浓度（2.5 ng/ml）。考虑到HGF是由卫星细胞和其他细胞对肌肉损伤的反应产生的，沐浴卫星细胞的局部HGF浓度可能达到足以诱导肌肉生长抑制素表达的阈值。在肌肉再生的初始阶段，这种时滞可能会延迟增殖细胞的负反馈信号的作用，因此，细胞外HGF浓度的时间协调增加是具有低阈值和高阈值的两种相反途径的关键调节剂。根据这一假设，细胞的激活和静止可能是一个以HGF对肌源性细胞的作用为中心的时间协调的事件序列。通过了解卫星细胞的“机械生物学”，我们将能够设计出新的程序，专门针对激活和静止来促进肌肉的生长和修复，为肉类动物生产、人类运动和健康科学做出贡献，旨在提高身体机能，并为肌肉萎缩症和与年龄有关的萎缩症提供医学治疗。

Skeletal muscle regeneration and work-induced hypertrophy rely on molecular events responsible for activation and quiescence of resident myogenic stem cells, satellite cells. The present studies of satellite cells in culture and in vivo demonstrated the essential role of hepatocyte growth factor (HGF) in the activation cascade of events including Ca-calmodulin complex formation, nitric oxide synthase (cNOS-1) activation, NO radical production, matrix metalloproteinase (MMP) activation, HGF release with associated extracellular segments of proteoglycans, and HGF binding to the high-affinity receptor, c-met. These experiments also revealed that HGF could induce satellite cell quiescence by stimulating myostatin expression, however, the HGF concentration required (over 10-50 ng/ml) is much higher than that for activation (2.5 ng/ml). Considering that HGF is produced by satellite cells and other 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 negative feedback signaling in proliferating cells during initial phases of muscle regeneration, therefore, the time-coordinated increase in extracellular concentrations of HGF is a key modulator for the two contrary pathways having low and high thresholds. According to this scenario, the cell activation and quiescence may be a temporally coordinated sequence of events centering on the actions of HGF on myogenic cells. By understanding the "mechano-biology" of satellite cells, we will be able to design new procedures that specifically target activation and quiescence to enhance muscle growth and repair, contributing to the meat-animal production and human sports and health sciences aimed to enhance physical performance and medical therapies for muscular dystrophy and age-related atrophy.