组蛋白甲基转移酶MLL4对骨骼肌纤维类型和代谢功能的调控作用与机制研究

骨骼肌是人体最大的运动和能量代谢器官。为应答运动与营养刺激，骨骼肌通过不断的调整肌纤维结构和代谢功能来维持机体的正常生理稳态，其结构和代谢功能紊乱则与500多种人类疾病相关。关于环境刺激诱导骨骼肌重塑的分子机制目前还不清楚。申请人曾发现骨骼肌线粒体质量控制对于运动能力和整体糖脂代谢至关重要。本项目前期通过研究基因敲除小鼠初步证实，增强子激活关键调节因子MLL4在运动与营养诱导肌纤维结构和代谢功能重塑中起重要调节作用。根据前期研究数据，我们推测：MLL4可能通过直接调控肌纤维结构类型和代谢功能来应答运动和营养刺激的变化，影响机体整体代谢。本课题拟从动物整体水平、细胞水平和分子水平系统研究MLL4表观遗传调节通路在不同外环境刺激诱导骨骼肌重塑中的功能及其作用过程。本课题的完成，将为探讨骨骼肌相关疾病和代谢疾病的防治新途径提供实验依据。

Skeletal muscle is the largest contraction and energy metabolism organ in human. In response to exercise and nutrient stimuli, skeletal muscle undergoes continuously structural and metabolic reprograming to maintain the normal physiological homeostasis. Skeletal muscle structural and metabolic dysfunction is link to more than 500 human diseases. The molecular mechanism underlying the skeletal muscle remodeling upon environmental stimuli remains unclear. We have previously demonstrated that defective muscle mitochondrial quality control play a crucial role in exercise capacity and systemic glucose and lipid metabolism. Analyses of knockout mice have suggested that the key regulators of enhancer activation, MLL4, is essential for exercise and nutrient-induced muscle structural and metabolic remodeling. Therefore, we propose that MLL4 may directly regulate muscle fiber type switch and metabolic function to meet exercise and nutrient stimulation changes, and affect systemic metabolism. To verify this hypothesis, we will analyze a series of animal model with physiological, molecular and cellular methods to elucidate the mechanistic actions of MLL4 epigenetic regulatory pathways in skeletal muscle remodeling upon different external environment stimuli. Completion of this project will provide innovative clues for prevention and intervention of skeletal muscle-related and metabolic diseases.