Long Term Aerobic Exercise Enhances Cardioprotective Effects Of Insulin Against Ischemia/reperfusion Induced Injury And Underlying Mechanisms

Objective: We have previously found that insulin acts as a protective agent applicable to ischemic/reperfused (I/R) myocardial tissue via activating the survival pathway, i.e., PI3K-Akt signaling. Physical activity was linked to the improved insulin sensitivity in peripheral insulin-targeted organs as skeletal muscle. However, the effects of aerobic exercise (AE) on cardiac insulin sensitivity are largely unclear. Therefore, the aims of this study were to determine whether long term AE increases the protective effects of insulin on I/R myocardium, and if so, to investigate the underlying mechanism.Methods: Adult male Sprague-Dawley (SD) rats were randomly subjected to 8-wk either sedentary or free-loading swimming exercise (3 h/d, 5 d/wk). Then the animals were subjected to 30 min MI followed by 4hr R.Results: MI/R caused significant cardiac dysfunction and myocardial apoptosis (strong TUNEL-positive staining). Compared with sedentary group, rats subjected to 8-wk AE and treated with insulin 5 min before reperfusion showed protection against MI/R as evidenced by reduced myocardial infarction (13.3%±3.38% vs.26.75.%±1.49% of sedentary plus insulin group, n = 6, P < 0.05), marked decrease apoptotic index (7.0%±1.8 % vs. 15%±2.6% of sedentary plus insulin group, n = 6, P < 0.05), significant decrease of plasma CK and LDH and improved recovery of cardiac systolic/diastolic function (including LVSP and± LV dP/dt) at the end of R. Moreover, long term AE resulted in 2-fold increase in Akt expression in myocardium (n=4, P < 0.05 vs. sedentary group); insulin resulted in 1.7-fold and 1.9-fold increase in Akt phosphorylation (Akt-ps473) and glycogen synthase kinase-3βphosphorylation, which was measured to evaluate Akt activation, in I/R myocardium of exercise animals, respectively (n = 4, all P < 0.05 vs. sedentary plus insulin group). Importantly, Treatment with PI3K (upstream molecule of Akt) inhibitor wortmannin 15 min before R not only significantly blocked both Akt phosphorylation and activity (n =6 ,P < 0.05), but also abolished long term AE-induced synergies with insulin on I/R myocardium as manifested by increased apoptosis, plasma CK and LDH, infarct size and reduced cardiac function ( P < 0.05).Conclusion: These results demonstrate that aerobic exercise enhances the cardioprotective effects of insulin on I/R myocardium via upregulationg Akt signaling cascades.