药学学报, 2021, 56(1): 190-200
引用本文:
张誉馨, 张锐, 杨静, 闪雪纯, 梁秀睿, 张怡, 徐凡, 金佳琦, 关晶, 傅继华. 2型糖尿病引起的疲劳与骨骼肌5-羟色胺降解的相关性研究[J]. 药学学报, 2021, 56(1): 190-200.
ZHANG Yu-xin, ZHANG Rui, YANG Jing, SHAN Xue-chun, LIANG Xiu-rui, ZHANG Yi, XU Fan, JIN Jia-qi, GUAN Jing, FU Ji-hua. Relationship between fatigue caused by type 2 diabetes mellitus and 5-HT degradation in skeletal muscle[J]. Acta Pharmaceutica Sinica, 2021, 56(1): 190-200.

2型糖尿病引起的疲劳与骨骼肌5-羟色胺降解的相关性研究
张誉馨, 张锐, 杨静, 闪雪纯, 梁秀睿, 张怡, 徐凡, 金佳琦, 关晶, 傅继华
中国药科大学基础医学与临床药学学院, 江苏 南京 210009
摘要:
疲劳是2型糖尿病(T2DM)常见的并发症。本文研究了T2DM性疲劳与骨骼肌5-羟色胺(5-HT)系统的关系。动物实验用高脂饲料喂养结合腹腔注射链脲佐菌素建立小鼠T2DM模型,用5-HT2A受体(5-HT2AR)拮抗剂盐酸沙格雷酯(SH)及5-HT合成抑制剂卡比多巴(CDP)分别或联合给药治疗。细胞实验用D-葡萄糖、棕榈酸或5-HT刺激C2C12细胞。用SH、CDP或单胺氧化酶A(MAO-A)抑制剂氯吉兰分别抑制5-HT2AR、5-HT合成及5-HT降解。本文中动物福利和实验过程均遵循中国药科大学动物伦理委员会的规定。结果表明,小鼠骨骼肌及C2C12细胞均存在5-HT2AR、5-HT合成酶及MAO-A表达。T2DM以及棕榈酸、D-葡萄糖刺激C2C12细胞时,它们的表达明显上调,且棕榈酸是比D-葡萄糖更敏感的刺激它们表达的因子。转棒实验及生化指标检测均表明,T2DM性疲劳起因于骨骼肌5-HT2AR、5-HT合成及5-HT降解的增加。5-HT2AR通过介导MAO-A表达、5-HT合成,间接调控5-HT降解。而MAO-A通过介导5-HT降解,调控细胞炎症、线粒体的ROS产生及膜电位去极化,还抑制过氧化物酶体增殖物激活受体-γ共激活因子-1(PGC-1)、肉碱棕榈酰转移酶1(CPT1)及ATP合成酶6(ATP6)表达,从而抑制线粒体功能,如脂肪酸β氧化和ATP合成。用SH和CDP可有效地治疗T2DM性疲劳,同时也可降血糖和血脂,且联合给药有明显的协同效应。
关键词:    糖尿病性疲劳      骨骼肌      5-HT2A受体      5-HT合成      线粒体5-HT降解      线粒体ATP合成     
Relationship between fatigue caused by type 2 diabetes mellitus and 5-HT degradation in skeletal muscle
ZHANG Yu-xin, ZHANG Rui, YANG Jing, SHAN Xue-chun, LIANG Xiu-rui, ZHANG Yi, XU Fan, JIN Jia-qi, GUAN Jing, FU Ji-hua
School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, China
Abstract:
Fatigue is a common complication of type 2 diabetes mellitus (T2DM). We examined the relationship between T2DM fatigue and the skeletal muscle 5-hydroxytryptamine (5-HT) system. In animal experiments, a T2DM model was established in mice by feeding a high-fat diet with intraperitoneal injection of streptozotocin. The mice were treated with the 5-HT2A receptor antagonist sarpogrelate hydrochloride (SH) and the 5-HT synthesis inhibitor carbidopa (CDP) (separately and in combination). In cell culture experiments, C2C12 cells were stimulated with D-glucose, palmitic acid or 5-HT. 5-HT2AR, 5-HT synthesis and 5-HT degradation were inhibited by SH, CDP, or monoamine oxidase A (MAO-A) inhibitor. The animal experiments were in accordance with the regulations of the Animal Ethics Committee of China Pharmaceutical University. The results showed that 5-HT2AR, 5-HT synthase and MAO-A were expressed in mouse skeletal muscle and C2C12 cells. The expression of these proteins was significantly up-regulated in T2DM mice or when C2C12 cells were exposed to palmitic acid and D-glucose; palmitic acid was a stronger stimulant of their expression than D-glucose. Rotating rod experiments and biochemical index tests have shown that T2DM fatigue is associated with an increase in skeletal muscle 5-HT2AR, 5-HT synthesis and 5-HT degradation. 5-HT2AR mediates the expression of MAO-A and the synthesis of 5-HT, which indirectly regulates the degradation of 5-HT. MAO-A regulates cell inflammation, mitochondrial ROS production and membrane potential depolarization by mediating 5-HT degradation. MAO-A also inhibits the expression of peroxisome proliferator-activated receptor γ coactivator-1 (PGC-1), carnitine palmitoyltransferase-1 (CPT1) and ATP synthase-6 (ATP6), thus inhibiting mitochondrial functions such as fatty acid β oxidation and ATP synthesis. SH and CDP can effectively treat T2DM fatigue, and can also reduce blood glucose and blood lipid, and the combination of SH and CDP has a clear synergistic effect.
Key words:    diabetes-related fatigue    skeletal muscle    5-HT2A receptor    5-HT synthesis    5-HT degradation in the mitochondria    ATP synthesis in the mitochondria   
收稿日期: 2020-08-24
DOI: 10.16438/j.0513-4870.2020-1403
基金项目: 国家自然科学基金资助项目(81570720);中国药科大学“双一流”学科创新团队建设项目(CPU2018GY23);江苏省研究生科研创新计划项目(KYCX19_0690).
通讯作者: 傅继华,E-mail:fjhfy_cpu@163.com
Email: fjhfy_cpu@163.com
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