LKB1/AMPK信号在骨骼肌卫星细胞老化过程中的作用与机制研究

近几年研究发现，微环境包括代谢等因素对骨骼肌卫星细胞的老化和干细胞属性具有重要影响，但对其作用途径及卫星细胞老化的分子机制了解很少；老化肌卫星细胞在合适条件下具有再年轻化潜能。LKB1/AMPK是调控细胞能量代谢和稳态的关键信号分子，热量限制等手段能增强老化肌卫星细胞功能活性。结合前期工作，我们认为LKB1/AMPK是介导微环境因素引起肌卫星细胞老化的重要途径。为此本课题将首先明确代谢应激对肌卫星细胞Lkb1/AMPK信号的调节；检测老化卫星细胞该信号途径的变化，通过特异活化和靶向敲除等方法重点研究Lkb1/AMPK信号对卫星细胞自我更新和增殖分化的影响，并探讨其作用的胞内信号途径；应用双向移植等手段观察微环境和细胞内AMPK信号对卫星细胞再生能力的影响。通过深入阐明肌卫星细胞老化的分子机制，探索恢复其自我更新和增殖分化潜能的抗衰策略，为防治增龄性骨骼肌丢失症等老年退行性疾病提供线索。

In recent years, studies have found that microenvironmental factors including metabolic state exert an important influence on the stem cell properties and the aging process of skeletal muscle satellite cells. But it remains elusive about the ways these factors work and the molecular and cellular mechanisms of satellite cell aging. Previous and our studies show that senescent satellite cells can be rejuvenated under appropriate conditions. LKB1/AMPK is a key signal in modulating cellular energy metabolism and homeostasis. Recent calorie restriction etc. works suggest that such kind of modulation can enhance the function of satellite cells. In combination with our preliminary work, we suppose LKB1/AMPK is an important pathway mediating the impact of some microenvironmental factors on satellite cells aging. For this reason, the project will first examine the effect of metabolic stress on the Lkb1/AMPK signal of muscle satellite cells. Then we’ll detect the changes of Lkb1/AMPK signal pathway in senescent satellite cells. The research will focus on the effects of Lkb1/AMPK signal on the self-renewal, proliferation and differentiation potential of aging satellite cells, through specific activation and targeted knockout method. And the effect of intracellular and microenvironmental Lkb1/AMPK signal on regenerative capability of satellite cells will be studied by application of bidirectional stem cell transplantation. We will further investigate the main intracellular downstream pathways involved in this process through specific intervention methods. By clarifying the cellular and molecular mechanism of skeletal muscle satellite cell aging, it will probably offer strategies for keeping or even recovering the self-renewal, proliferation and differentiation potential of satellite cells, and further provide effective prevention and therapeutic clues for the sarcopenia and other aging-related degenerative diseases.