Long-term impact of postnatal overfeeding on sensitivity to ischemia-reperfusion injury in vivo and on cardio-metabolism risk

Abstract

Nutritional disturbances during the postnatal period may be responsible for a predisposition, or “programming”, to increased cardio-metabolic risk and to a progressive alteration of left ventricular contractility in adulthood. However, these data have mainly obtained in young male mice, but less is known for older animals. Our aim was to evaluate the impact of postnatal overfeeding (PNOF) on cardiac function, on cardiac sensitivity to ischemia-reperfusion (I-R) injury in vivo and on glucose metabolism in young (4 months), adult (6 months) and old (12 months) male mice. PNOF was induced by the reduction of litter size of C57/BL6 mice immediately after birth: normally-fed group (NF) was composed of 9 male pups/mother and overfed group (OF) of 3 pups/mother. Echocardiography and blood sugar tests have been performed at all ages. An in vivo ischemia-reperfusion injury was induced by the ligation of the anterior interventricular artery for 45 minutes followed by 24 h of reperfusion. All experiments have been done on 4-, 6- and 12-months aged male mice. PNOF induced an early and permanent increase in body weight in OF group, independently of mice's age (+23% at 24 days of life, +14% at 4 months, +23% at 6 and 12 months, compared to NF group). The echocardiographic measurements showed an alteration of contractile function from 6 months aged males and up to 12 months as evidenced by a decrease of the left ventricular ejection fraction (−11% for OF males from 6 to 12 months, compared to NF groups). These cardiac alterations were associated with glucose metabolism imbalance: OF males presented glucose intolerance and insulin resistance from 4 to 12 months of age. To finish, PNOF induced a significant increase of infarct size at 4 months (+37%, P < 0.01, n = 8), 6 months (+32%, P < 0.05, n = 9) and 12 months (+38%, P < 0.05, n = 9) after cardiac surgery. Nutritional programming through short-term PNOF induced an early alteration of glucose metabolism and was associated with a constant higher susceptibility to myocardial I-R injury in vivo. Moreover, PNOF mice developed altered cardiac contractility at 6 months and up to 12 months. The cellular and biochemical mechanism of these pathological modifications induced by PNOF need further exploration but could involve alterations in cardiomyocyte pathways, and/or modification of global inflammatory status.