骨骼肌分化新调控因子mGPDH在糖尿病肌病中的作用与机制研究

Diabetes mellitus is prone to skeletal muscle regeneration deregulation, which leads to diabetic myopathy (DMs), and its mechanism remains unclear. Our research group found that the expression of a key components of respiratory chain glycerol phosphate shuttle--mitochondrial glycerol dehydrogenase (mGPDH) was dynamic increase in the skeletal muscle differentiation process, knockdown of mGPDH prevents or delay skeletal muscle cell differentiation and maturation, and in animal models of diabetes mellitus, its expression was significantly reduced, suggesting that mGPDH may be involved in the regulation of differentiation of skeletal muscle cells, the reduction may be an important cause of DMs skeletal muscle regeneration disorder. The project intends to study the regeneration of skeletal muscles within mdx rats (which is the classical model of skeletal muscle regeneration insufficiency) and mGPDH-/- rats, to explore its downstream signaling pathway (previously found that may be associated with CaMKK beta /AMPK); in the further step, the mGPDH-/-db/db diabetes rats will be used to explore the role of mGPDH in the formation of DMs, and the possibility of becoming an effective target of DMs intervention. Thus to reveal the relationship between mGPDH and the maintenance of skeletal muscle cell function, and to analyze the cascade signal system, in order to understand the mechanism of DMs and provide new strategies for the intervention.

糖尿病易并发骨骼肌再生障碍，从而引致糖尿病肌病（DMs），其具体成因不清。课题组前期发现呼吸链甘油磷酸穿梭关键组分——线粒体甘油磷酸脱氢酶（mGPDH）在骨骼肌分化过程中呈动态升高，敲低mGPDH则阻抑骨骼肌细胞分化成熟，且在糖尿病动物模型内其表达显著下调，提示：mGPDH可能参与骨骼肌细胞的分化调控，其下调可能是DMs时骨骼肌再生障碍的重要成因。故项目拟于课题组已有的骨骼肌再生缺乏经典模型mdx鼠以及mGPDH-/-鼠内，阐述mGPDH对骨骼肌分化过程的调控，寻找其下游信号传递途径（前期已发现可能与CaMKKβ/AMPK相关）；进而经mGPDH-/-db/db糖尿病鼠，探讨其在DMs形成中的作用，及其成为DMs有效干预靶点的可能性。从而揭示mGPDH与骨骼肌细胞功能维持关联，解析其信号级联机制，旨在深入理解 DMs发生机理，为其干预提供新的策略与依据。

虽然成年哺乳动物骨骼肌由于其有丝分裂后的特性而稳定，但肌肉再生在整个生命周期中对于维持功能适应性仍然是必不可少的。在发生某些疾病时，如世界范围内大流行的慢性疾病—肥胖症和糖尿病，肌肉再生过程会受到损害，从而导致肌肉功能的丧失，并加重这些疾病的全球负担。肌萎缩是肥胖及糖尿病常见且易被忽视的并发症之一，其表现为肌肉重量、力量以及运动耐量的减低。然而其发病机制并不清楚，本项目研究发现，线粒体蛋白mGPDH在糖尿病、肥胖动物模型及患者的骨骼肌中表达减低，该种缺乏可能通过影响线粒体生物合成关键因子PGC1的活性，经AMPK/CAMPKK通过调控线粒体能量代谢，调节肌源性标记物和成肌细胞分化，从而减慢骨骼肌损伤后的修复过程，参与糖尿病与肥胖相关肌萎缩的发生发展，严重影响糖尿病及肥胖患者的运动能力。而通过AAC9-mGPDH局部注射的方式回复mGPDH的表达，则可显著改善糖尿病及肥胖所致骨骼肌损伤后再生障碍及运动耐量减退。因此，靶向线粒体蛋白mGPDH可能参与糖尿病或肥胖相关肌病的发病与进展，而我们的研究为肥胖和糖尿病骨骼肌再生障碍提供了一个潜在的治疗靶点。