Low intrinsic aerobic exercise capacity and systemic insulin resistance are not associated with changes in myocardial substrate oxidation or insulin sensitivity

In patients, inactivity, obesity and insulin resistance are associated with increased incidence of heart failure. Rats selectively bred for low (LCR) intrinsic aerobic exercise capacity show signs of the metabolic syndrome including insulin resistance, compared to their counterparts bred for high intrinsic aerobic capacity (HCR). We reasoned that systemic insulin resistance in LCR should translate to impaired substrate oxidation and reduced insulin sensitivity in the heart. Isolated hearts were perfused in the working mode to analyze cardiac function, substrate oxidation patterns, insulin response, and oxygen consumption. After 22 generations of selective breeding, LCR displayed reduction of exercise capacity (LCR vs. HCR: distance 280 ± 12 vs. 1,968 ± 63 m, time 19.5 ± 0.6 vs. 71.7 ± 1.4 min, speed 19.2 ± 0.3 vs. 45.3 ± 0.7 m/min; all p < 0.05). At 21 weeks, body weight (+34%), tibia length (+6%), heart weight (+31%), and heart weight to tibia length ratio (+24%; all p < 0.05) were increased. LCR display higher random glucose, higher fasting glucose, and higher insulin levels in serum than HCR indicating the presence of insulin resistance in LCR. Here, in contrast, isolated hearts showed no differences in glucose (0.22 ± 0.02 μmol/min/g dry) or fatty acid oxidation (0.79 ± 0.10 μmol/min/g dry), oxygen consumption (28.3 ± 4.1 nmol O₂/min/g dry) or cardiac power (18.6 ± 1.6 mW/g dry). Furthermore, sensitivity to insulin (Δglucose oxidation: +0.57 ± 0.095 μmol/min/g dry) was not different between the two populations. Low intrinsic exercise capacity and systemic insulin resistance in rats are not associated with changes in cardiac substrate oxidation, insulin sensitivity, oxygen consumption, or cardiac function. The lack of cardiac insulin resistance in the face of systemic insulin resistance supports a concept of different pathomechanisms for these two conditions.