Abstract
Myocardial fibrosis can trigger heart failure in diabetic cardiomyopathy (DCM), and irisin, an exercise-induced myokine, may have a beneficial effect on cardiac function. However, the specific molecular mechanism between exercise and irisin in the diabetic heart remains not fully explored. This study aimed to investigate how miR-34a mediates exercise-induced irisin to ameliorate myocardial fibrosis and its underlying mechanisms. Type 2 diabetes mellitus (T2DM) with DCM was induced in adult male rats with high-fat diet and streptozotocin injection. The DCM rats were subjected to swimming (60 min/d) and recombinant irisin (r-irisin, 500 μg/kg/d) interventions for 8 weeks, respectively. Cardiac function, cardiomyocyte structure, myocardial fibrosis and its correlated gene and protein expression were analyzed. Swimming intervention alleviated insulin resistance, myocardial fibrosis, and myocardial hypertrophy, and promoted blood glucose homeostasis in T2DM model rats. This improvement was associated with irisin upregulation and miR-34a downregulation in the myocardium, thus enhancing cardiac function. Similar efficacy was observed via intraperitoneal injection of exogenous recombinant irisin. Inhibition of miR-34a in vivo exhibited an anti-myocardial fibrotic effect by promoting irisin secretion through activating sirtuin 1 (SIRT1)/peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α)/fibronectin type III domain-containing protein 5 (FNDC5) signal pathway and downregulating myocardial fibrosis markers (collagen I, collagen III, and transforming growth factor-β1). Therefore, swimming-induced irisin has the potential therapeutic effect on diabetic myocardial fibrosis through activating the miR-34a-mediated SIRT1/PGC-1α/FNDC5 signal pathway.
Funder
National Natural Science Foundation of China
Natural Science Foundation of Hubei Province
Education Department of Jiangxi Province
Publisher
Public Library of Science (PLoS)
Reference58 articles.
1. Molecular mechanisms of diabetic cardiomyopathy;H Bugger;Diabetologia,2014
2. Diabetic cardiomyopathy—A comprehensive updated review;G Murtaza;Progress in cardiovascular diseases,2019
3. IDF diabetes atlas: Global estimates of undiagnosed diabetes in adults for 2021;K Ogurtsova;Diabetes research and clinical practice,2022
4. Exogenous hydrogen sulfide plays an important role by regulating autophagy in diabetic-related diseases;S Lv;International journal of molecular sciences,2021
5. Diabetic cardiomyopathy;WH Dillmann;Circulation research,2019