11β-HSD1调控肌肉干细胞在老年肌少症中的分子机理研究

Sarcopenia has risen to be an important topic which is the potential risk factor for weak ,disability and death of the elderly. The decline of skeletal muscle stem cell self-renewal and differentiation ability play a key role in the development of sarcopenia. As we all know, calorie restriction is the effective anti-aging means, but the mechanism is unclear. It is reported that glucocorticoid(GC) level is closely related to aging and sarcopenia. In our previous study, the expression of 11β-HSD1 genes of muscle tissue increased with aging. In response to CR, the expression of 11β-HSD1 genes decreased, muscle aging delayed. We also found 11β-HSD1 inhibtor (already synthesized) can reverse differentiation ability of muscle stem cell treated with free fatty acid. Therefore, we speculated 11β-HSD1 was the caloric restriction target. In this proposal, we innovatively studied the role of 11β-HSD1 in regulating the miRNA expression and improving muscle stem cell function in order to find out the mechanisms of caloric restriction. Accordingly, we synthesised the 11β-HSD1 inhibitor to develop caloric restriction mimetics in order to provide therapeutic target of anti-aging and delaying sarcopenia.

肌少症是老年人衰弱、失能及死亡的重要危险因素，肌肉干细胞更新及分化能力下降在老年肌少症中起关键作用。众所周知，热卡限制是最经典有效的延缓器官功能衰退的手段，但机制不清。文献报道，糖皮质激素（GC）水平增加与促进老化及肌少症密切相关，调控GC的局部浓度可能是调节衰老进程的关键步骤。我们前期研究发现：作为调控局部组织GC活性的关键酶，肌肉组织的11β-羟化类固醇脱氢酶1（11β-HSD1）在老化时表达明显升高，而热卡限制可下调其表达、延缓肌肉老化；体外实验发现11β-HSD1抑制剂（已自行合成）可改善受损的肌肉干细胞分化能力。因而，为了明确11β-HSD1是热卡限制的作用靶点，本课题从11β-HSD1调控启动子具有GC受体反应元件（GRE）的miRNA，改善肌肉干细胞功能入手，搞清热卡限制延缓老年肌少症的分子机制；并通过11β-HSD1抑制剂干预研究，为临床有效抗衰老、延缓肌少症提供新手段。

与年龄相关的骨骼肌质量和功能的进行性损失被称为肌肉减少症，并增加了成人个体对不良临床结果的易感性。目前，尚无有效的肌肉减少症治疗方法，治疗仅限于改善营养和加强锻炼。众所周知，肌肉干细胞(muscle stem cells, MuSCs)主要负责骨骼肌的再生。随着年龄的增长，MuSCs的增殖和分化能力显著下降，导致衰老个体的肌肉再生受损。因此，提高MuSCs的功能是延缓肌肉减少症的有效途径。热卡限制（Calorie restriction, CR）不仅可以减少脂肪堆积，改善胰岛素抵抗，还可以维持器官功能，具有抗衰老作用。然而，CR抗衰老的具体机制尚不清楚。在此次研究中，我们首先构建成功了几个小鼠模型，自然衰老的小鼠、肌肉特异性11β-HSD1敲除和高表达11β-HSD1鼠, 进一步利用热卡限制作为代谢干预模型。我们的研究已经发现：11β-HSD1的水平升高是衰老肌肉的标志；老年小鼠进行热卡限制可通过11β-HSD1降低GC局部有效浓度，促进MuSCs的线粒体功能和分化能力，从而延缓衰老小鼠的肌肉萎缩; 年轻小鼠的高表达11β-HSD1会促进肌肉萎缩；肌肉特异性11β-HSD1敲除可挽救老年性的肌肉萎缩。我们的研究结果强调了40%CR对延缓老年肌少症是有希望的一种方法，提示11β-HSD1可能通过代谢调节延缓肌肉减少症的发生，靶向11β-HSD1依赖的代谢途径可能为开发治疗肌少症的新策略。