TLR9诱导前脂肪细胞增殖与分化参与老年肌少症发生的机制研究

Sarcopenia is an geriatric syndrome characterized with the loss of muscle mass and dysfunction with aging. which increases the risk of disability in the elderly. Ectopic fat deposition, recognized as an crucial pathological process in sarcopenia, has adverse effects on quantity and strength of skeletal muscle. Preadipocytes, of regenerative potential, are the main source of excessive fat deposition in skeletal muscle, and Per3 plays an important role in this process. Previous studies have revealed that activation of TLR9 is closely related to obesity and nonalcoholic steatohepatitis. And TNF-α,a key inflammatory mediator released by TLR9 stimulation, has been proved to significantly suppress Per3 transcription. In the preliminary experiment, we found that TLR9 can negatively regulate the expression of Per3, with awful effects, such as the increase of fat accumulation and decrease of muscle strength. Therefore, we speculate that TLR9 is involved in the occurrence of ectopic fat deposition in sarcopenia, which partially depends on the activation of TLR9/TNF-α pathway on per3 to promote the regeneration and differentiation of Preadipocytes. To prove our speculation, we intend to use TLR9 knock-out mice and lentivirus transfection to selectively regulate expression of TLR9,TNF-α,Per3 to see the alteration of fat infiltration in skeletal muscle. It may be of significant to elucidate molecular mechanism of ectopic fat deposition in skeletal muscle, eventually to provide new clues for the further study of sarcopenia.

老年肌肉减少症（肌少症）是衰老过程中以骨骼肌质量减少及功能减退为特征的老年综合症，增加老年人失能风险。骨骼肌异位脂肪沉积从多方面影响骨骼肌质量及功能，促进肌少症的发生。具有再生潜力的前脂肪细胞增殖及分化是骨骼肌内脂肪堆积的重要来源，生物钟基因Per3在这一过程中担任重要角色。既往研究表明TLR9激活促进肥胖、非酒精性脂肪肝的发生，下游炎症因子TNF-α抑制Per3转录。在前期工作观察到TLR9具有负性肌力、增加小鼠体内脂肪堆积的特点，并负向调控Per3。由此我们推测TLR9参与了老年肌少症骨骼肌脂肪异位沉积的发生，其机制可能与TLR9/TNF-α通路干扰per3介导的前脂肪细胞增殖分化有关。本项目首次探讨TLR9在肌少症骨骼肌脂肪异位沉积中的作用，从定向干细胞增殖分化角度入手，以期阐明肌少症骨骼肌异位脂肪沉积的可能分子机制，为防治该病提供新思路、新线索。

老年肌肉减少症（肌少症）是衰老过程中以骨骼肌质量减少及功能减退为特征的老年综合症，增加老年人失能风险。骨骼肌异位脂肪沉积从多方面影响骨骼肌质量及功能，促进肌少症的发生。具有再生潜力的前脂肪细胞增殖及分化是骨骼肌内脂肪堆积的重要来源，生物钟基因Per3在这一过程中担任重要角色。既往研究表明TLR9激活促进肥胖、非酒精性脂肪肝的发生，下游炎症因子TNF-α抑制Per3转录。在前期工作观察到TLR9具有负性肌力、增加小鼠体内脂肪堆积的特点，并负向调控Per3。由此我们推测TLR9参与了老年肌少症骨骼肌脂肪异位沉积的发生，其机制可能与TLR9/TNF-α通路干扰per3介导的前脂肪细胞增殖分化有关。本项目首次探讨TLR9在肌少症骨骼肌脂肪异位沉积中的作用用，从定向干细胞增殖分化角度入手，以期阐明肌少症骨骼肌异位脂肪沉积的可能分子机制，为防治该病提供新思路、新线索。成功通过D-半乳糖法构建快速衰老模型小鼠及体外肌细胞衰老模型，已完成LOXL2在肌少症发生发展中作用的机制性探讨。同时也完成了lncRNA GM20743调控肌少症的铁死亡过程中的机制探讨。已完成TLR9基因在糖尿病脑病小鼠中作用的机制探讨。

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