中药菩人丹调节骨骼肌蛋白质合成-分解代谢失衡干预老年2型糖尿病肌少症的作用机制研究

肌少症是严重影响老年T2DM患者生活质量的慢性并发症。临床研究发现T2DM患者肌力和肌质量显著下降，肌脂比严重失衡，而骨骼肌质量取决于蛋白质合成分解代谢。课题组在前期研究中发现菩人丹可调控PI3K/Akt-mTOR和FoxO等蛋白质代谢相关信号通路，抑制骨骼肌细胞凋亡。在此基础上，本项目以老年T2DM大鼠为研究对象，考察骨骼肌蛋白质合成分解速率、BCAA及氨基酸转运、蛋白质代谢通路等变化，阐明老年T2DM蛋白质代谢失衡规律，同时，利用单细胞测序构建单细胞图谱、发现关键细胞类型和新型细胞标记物，揭示菩人丹治疗T2DM肌少症的分子及细胞机制。提出并验证假说：“维持骨骼肌蛋白质代谢平衡是治疗T2DM肌少症的关键，促进mTOR介导的蛋白质合成，抑制泛素蛋白酶系统介导的蛋白质过度分解，是养阴清热、健脾益气中药菩人丹治疗T2DM肌少症的核心”，进而为“脾主肌肉”理论治疗老年T2DM肌少症提供实验依据。

Sarcopenia is a chronic complication of T2DM that severely reduces the quality of life in the elderly. Clinical researches showed that more serious muscle wasting and unbalanced muscle fat rat were found in T2DM patients. As known, skeletal muscle mass depends on protein metabolism. Previous studies have found that the TCM prescription Pu-Ren-Dan can regulate PI3K/Akt-mTOR and FoxO signaling pathways, and inhibit apoptosis of muscular cell. On this basis, this study will investigate the effects of Pu-Ren-Dan on T2DM skeletal muscle protein metabolism, skeletal muscle protein synthesis and degradation rate, BCAA and amino acid transporter, protein metabolism pathways in the elderly T2DM rats, in order to clarify the imbalance of protein metabolism in elderly T2DM patients. Meanwhile, to reveal the cellular mechanism of Pu-Ren-Dan in the treatment of sarcopenia in T2DM, single-cell sequencing (SCS) will be used to construct single cell map and found the key cell types and novel cell markers. We hypothesized that maintaining the balance of skeletal muscle protein metabolism is the key to the treatment of sarcopenia in T2DM, and Pu-Ren-Dan can promote mTOR mediated protein synthesis and inhibit ubiquitin-proteasome pathway mediated protein excessive degradation. This study will provide a scientific basis for the theory of “spleen controlling muscle” applying in elderly T2DM sarcopenia.