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激活和静止的分子事件。目前对卫星细胞在培养和体内的研究表明，肝细胞生长因子（HGF）在包括Ca-钙调蛋白络合物形成，一氧化氮合酶（CNOS-1）激活，无自由基生产，Matrix Metraplans（MMP）激活，HGF的激活中的激活级联反应，HGF释放，HGF释放，HGF均无术， HGF与高亲和力受体C-MET结合。这些实验还表明，HGF可以通过刺激肌抑制素的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）远高于激活（2.5 ng/ml）。考虑到HGF是由卫星细胞和其他细胞响应肌肉损伤产生的，因此HGF沐浴卫星细胞的局部浓度可能达到足以诱导肌抑制素表达的阈值。这种时间滞后可能会在肌肉再生的初始阶段延迟反馈信号传导在增殖细胞中的作用，因此，HGF细胞外浓度的时间协调的增加是两个具有低阈值和高阈值的相反途径的关键调节剂。根据这种情况，细胞的激活和静止可能是以HGF对肌源性细胞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”，我们将能够设计新的程序，这些程序专门针对激活和静止以增强肌肉的生长和修复，从而有助于肉类动物的生产以及旨在增强身体性能和医学疗法的人类体育和健康科学，以促进肌肉营养不良和年龄较低的良心。