AMPK-JLP信号轴在调控p38MAPK活性及肌肉分化再生中的作用与机制研究

骨骼肌不仅是运动系统的重要组成部分，在人体代谢稳态维持中也发挥关键作用。骨骼肌的损伤再生依赖于成肌细胞的增殖和分化。在肌肉再生过程中，支架蛋白JLP通过调控p38MAPK的活性，来促进成肌细胞分化，但其上游调控机理尚不清楚。申请人前期预实验发现，成肌细胞分化中激活的AMPK与JLP发生相互作用，并直接影响JLP的亚细胞定位；进而发现JLP的第716位丝氨酸是潜在的AMPK磷酸化位点；而将该位点突变为丙氨酸后，JLP的亚细胞定位不受AMPK控制，且该突变体对p38MAPK的激活能力显著下降。在此基础上，我们计划阐明AMPK介导的S716位点磷酸化调控JLP功能的分子机制；解析AMPK调控JLP亚细胞定位的细胞学机理；在体内验证AMPK介导的JLP磷酸化对肌肉再生的影响。本项目的开展有助于阐明成肌分化中AMPK-JLP信号轴的作用及分子机制，并有望为开发肌肉相关疾病的治疗手段提供新的干预靶点。

Skeletal muscle plays important roles in modulating both physical performance and metabolic homeostasis. Skeletal muscle regeneration is dependent on the proliferation and differentiation of myoblasts. During muscle regeneration, the scaffold protein JLP activates p38MAPK to promote myoblast differentiation, while the upstream regulatory mechanism remains elusive. Here we found that AMPK interacted with JLP and directly regulated its subcellular localization during myoblast differentiation. We further identified that the Ser716 of JLP is a potential phosphorylation site of AMPK. Once the Ser716 residue was replaced by an Ala, the subcellular localization of JLP was resistant to AMPK-mediated regulation. Moreover, the Ser-to-Ala mutation impaired the ability of JLP to activate p38MAPK. We aim to further elucidate the molecular mechanism by which the Ser716 phosphorylation regulates the function of JLP, to reveal how AMPK modulates the subcellular localization of JLP, and to verify the physiological functions of AMPK-JLP axis in muscle regeneration. Our study will provide a new therapeutic target for treatment of muscle-related diseases.