CREG在肥胖导致的骨骼肌再生障碍中的作用及机制研究

肥胖患者骨骼肌再生障碍导致骨骼肌大量流失。骨骼肌再生依赖肌卫星细胞（Satellite cell，SC）的分化，但肥胖时SC分化的关键调控因子尚未阐明。CREG基因具有促进多种细胞分化的作用。我们近期研究发现，CREG与肥胖小鼠骨骼肌再生能力降低相关；在细胞模型中，过表达CREG可挽救棕榈酸对成肌细胞分化的抑制，提示CREG可能参与SC分化的调控。因此，本研究拟利用SC特异性CREG转基因及基因敲除小鼠，建立肥胖诱导的骨骼肌再生障碍模型，明确CREG是否通过调控SC分化参与肥胖时骨骼肌再生障碍的发生；并在体外建立棕榈酸诱导的SC分化抑制模型，探讨CREG是否通过与转录因子YY1结合发挥作用；最后利用自主制备的CREG-Fc融合蛋白，探讨其作为肥胖患者骨骼肌再生障碍治疗靶点的可能性。本研究将有望阐明调控肥胖所致骨骼肌再生障碍的关键因子。

Impaired skeletal muscle regeneration frequently occurs in obesity patients, which leads to a large loss of skeletal muscle. Skeletal muscle regeneration is based on the differentiation of satellite cells (SC), but the key regulators of SC differentiation during obesity have not been fully elucidated. CREG gene is found to promote differentiation of several cell types. Our recent studies show that decreased CREG is associated with reduced skeletal muscle regeneration in obese mice; moreover, overexpression of CREG can rescue the decreased differentiation of myoblast induced by palmitic acid in vitro, suggesting that CREG may be involved in the regulation of SC differentiation. Therefore, this study will employ SC-specific CREG transgene and knockout mice to establish a model of obesity-induced dysfunctional skeletal muscle regeneration, and determine whether CREG participates in the occurrence of impaired skeletal muscle regeneration during obesity by regulating SC differentiation. By establishing an in vitro model of palmitic acid-induced SC differentiation, we aim to explore whether CREG exerts its role through binding with the transcription factor YY1. Finally, the self-prepared CREG-Fc fusion protein is used to explore its potential as a therapeutic target for impaired skeletal muscle regeneration in obese mice. This study will hopefully find new key regulatory factors for impaired skeletal muscle regeneration during obesity.