Author + information
Exercise benefits lots to prevention and prognosis of cardiovascular diseases, however, so far, the exact molecular mechanism of which mediates this process is still unknown. Exercise facilitates gene FNDC5 expression and secretes more Irisin, a kind of myokines which can drive brown-fat-like development of white fat and thermogenesis, in myocardium and skeletal muscle. The currently study was to identify the effects of Irisin on glucose uptake and glucose utilization in hearts, to confirm Irisin protects the heart from I/R injury and to illuminate the mechanism of these process.
Construction of (Irisin deficiency) FNDC5 knockout mice, established myocardial ischemia/reperfusion (I/R) injury model. Myocardial tissues were collected to detect the expression of the correlation signal, analyze systolic and diastolic function at different time points after reperfusion. Working-Heart Perfusion System was used to detect myocardial glucose and fatty acid metabolism, glycolysis and glucose uptake.
We utilized Working-Heart Perfusion System to investigate the impact of Irisin on cardiac glucose utilization in a mouse model of Irisin deficiency (FNDC5 knockout). A significant reduction of glucose uptake and glucose oxidation were observed in KO hearts after reperfusion.
Mitochondrial pyruvate and malate supported complex I respiration and the respiratory control ratio were significantly reduced in the KO mice compared with WT mice.
At 10 min before reperfusion, mice were managed with Irisin intraperitoneal injection. Our data demonstrated that Irisin significantly increased glucose uptake and PDH activity both in KO and WT mice.
Our data demonstrated that AMPK inhibitor significantly blocked the facilitation effect of Irisin on glucose uptake. We used Akt inhibitor, FoxO1 and PDK4 gene over-expression successfully block modulating effects of Irisin on glucose oxidation.
Our data indicated that the KO hearts show increased sensitivity to I/R injury compared with WT herats. Consistent with our hypothesis, treating the hearts with Irisin 10 min before reperfusion significantly decreased myocardial injury.
Our previous data demonstrated that KO hearts show disturbed glucose utilization and increased sensitivity to I/R injury, meanwhile Irisin could promote glucose utilization and decrease I/R injury, which suggested us that Glucose utilization may play an causative role in I/R injury. Concordant with our hypothesis, enhancing glucose utilization by DCA also significantly decreased I/R injury.
In present study we demonstrated that Irisin plays an important role in regulating glucose metabolism in the heart and Irisin facilitating glucose uptake through APMK-GLUT4 Signaling and modulating PDH activity through Akt-FoxO1-PDK4 Signaling protects hearts from ischemia/reperfusion injury. Our results, therefore, reveal a critical role of Irisin in regulating cardiac metabolism and stress response.