Does size matter? Focus on the impact of reducing litter size in mice on cardio-metabolic risk and cardiac sensitivity to in vivo ischemia in adulthood

Abstract

Nutritional disturbances during the postnatal period may be responsible for a predisposition, or “programming”, of increased cardio-metabolic risk in adulthood. Reducing rodent litter size is therefore crucial for perinatal nutrition that may impact long-term health. However, few data are available concerning long lasting effects of postnatal overfeeding (PNOF) in mature and/or very old animals. Our aim was to evaluate the impact of PNOF on cardiac function, cardiac sensitivity to ischemia-reperfusion (I-R) injury in vivo and on glucose metabolism in young (4 months), adult (6 months), old (12 months) and very old (18 months) male mice. PNOF was induced by litter size reduction of C57/BL6 mice 2 days 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 (glucose tolerance and insulin resistance) 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. PNOF induced an early and permanent increase of 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, +10% at 18 months compared to NF group). The echocardiographic measurements showed an alteration of contractile function from 6 months aged males and up to 18 months as evidenced by a decrease of the left ventricular ejection fraction (−11% for OF males from 6 to 18 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. Finally, 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 early and long-lasting (up to 12–18 months) alterations of glucose metabolism and of cardiac contractility. Moreover, mice submitted to PNOF developed higher susceptibility to myocardial I-R injury in vivo at any age. Therefore, litter size is a strong determinant of long-term metabolic and cardiac status. Accordingly, adjusting litter size in rodent's group may be a necessary prerequisite in experimental procedures aimed at evaluating cardio-metabolic function.