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

常驻肌源干细胞激活和静止的分子机制及其通过功能性食品成分的可能调节

基本信息

批准号：
19380152
负责人：
TATSUMI Ryuichi
金额：
$ 12.4万
依托单位：
Kyushu University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2007
资助国家：
日本
起止时间：
2007 至 2009
项目状态：
已结题

项目摘要

Skeletal muscle regeneration and work-induced hypertrophy rely on molecular events responsible for activation and quiescence of resident myogenic stem cells, satellite cells. 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.

骨骼肌再生和工作诱导的肥大依赖于负责常驻肌源性干细胞（卫星细胞）的激活和静止的分子事件。目前的卫星细胞在培养和体内的研究表明，肝细胞生长因子（HGF）在激活级联事件，包括钙-钙调蛋白复合物的形成，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，释放相关的细胞外部分的蛋白聚糖，和HGF结合的高亲和力受体，c-met的重要作用。这些实验还揭示了HGF可以通过刺激肌生长抑制素表达来诱导卫星细胞静止，然而，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响应于肌肉损伤而产生的，HGF浸浴卫星细胞的局部浓度可能达到足以诱导肌生长抑制素表达的阈值。这种时滞可能会延迟肌肉再生初始阶段增殖细胞中负反馈信号的作用，因此，HGF细胞外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。根据这种情况，细胞活化和静止可能是以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”，我们将能够设计专门针对激活和静止的新程序，以促进肌肉生长和修复，为肉类动物生产和人类运动和健康科学做出贡献，旨在提高身体表现和肌肉萎缩症和年龄相关性萎缩的医学治疗。