Abstract 1651: Exercise Improves Aging-associated Myocardial Insulin Resistance by Enhancing Mitochondrial Function in an eNOS Dependent Mechanism
Objective. This study sought to determine whether exercise reduces aging-associated myocardial insulin resistance, with a specific focus on the role of eNOS and its relation to mitochondria.
Methods. Aging male Sprague-Dawley rats (24 months) were subjected to swim training (60 min/d, 5 d/wk, 9 wk) or assigned as sedentary control. The myocardial contraction, myocardial glucose uptake, mitochondrial function, and eNOS signaling were determined.
Results. Aging rats had myocardial insulin resistance as shown by decreased insulin-induced glucose uptake (0.22±0.05 μmol/min/g in aging heart vs.1.29 ± 0.13 μmol/min/g in adult heart, n=8, P<0.01) and attenuated insulin’s positive inotropic role as evidenced by reduced left ventricular developed pressure (90±12 mmHg in aging heart vs. 155±14 mmHg in adult heart, P<0.01). Mitochondrial function was decreased in aging hearts as manifested by the attenuated maximum O2 consumption by FCCP (1.85±0.39 μmol/min/g in aging hearts vs. 3.72±0.40 μmol/min/g in adult hearts, P<0.01). This was accompanied with the reduced insulin-induced O2 consumption (1.37±0.31 μmol/min/g in aging heart vs. 2.35±0.31 μmol/min/g in adult heart, P<0.01). In addition, eNOS expression and its phosphorylation by insulin were reduced by 1.2- and 2.3-fold in aging heart, respectively (P<0.01). Swim training upregulated eNOS expression by 72% (P<0.01), facilitated eNOS phosphorylation by insulin (P<0.01), and improved myocardial insulin sensitivity as shown by enhanced glucose uptake by insulin (P<0.01). Moreover, mitochondrial function was facilitated as manifested by the enhanced O2 consumption by insulin (P<0.05), and maximum O2 consumption (P<0.01) following swim training. Pretreatment with Cavtratin, an eNOS inhibitor, abolished exercise-improved mitochondrial response to insulin, blocked exercise-improved myocardial insulin sensitivity and the positive inotropic response to insulin in aging heart.
Conclusion. These results demonstrate that impaired eNOS signaling and subsequent mitochondrial depression is a major mechanism contributes to aging-associated myocardial insulin resistance, and that exercise improves insulin sensitivity by restoring eNOS signaling and enhancing mitochondrial function.