Relationship between fatigue caused by type 2 diabetes mellitus and 5-HT degradation in skeletal muscle
10.16438/j.0513-4870.2020-1403
- VernacularTitle: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
- Author:
Yu-xin ZHANG
;
Rui ZHANG
;
Jing YANG
;
Xue-chun SHAN
;
Xiu-rui LIANG
;
Yi ZHANG
;
Fan XU
;
Jia-qi JIN
;
Jing GUAN
;
Ji-hua FU
- Publication Type:Research Article
- Keywords:
iabetes-related fatigue;
skeletal muscle;
5-HT2A receptor;
5-HT synthesis;
5-HT degradation in the mitochondria;
ATP synthesis in the mitochondria
- From:
Acta Pharmaceutica Sinica
2021;56(1):190-200
- CountryChina
- Language:Chinese
-
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.
