Maternal voluntary exercise mitigates oxidative stress and incidence of congenital heart defects in pre‐gestational diabetes

Abstract

Women with pre‐gestational diabetes have a higher risk of producing children with congenital heart defects (CHDs), caused predominantly by hyperglycemia‐induced oxidative stress. In this study, we evaluated if exercise during pregnancy could mitigate oxidative stress and reduce the incidence of CHDs in the offspring of diabetic mice. Female mice were treated with streptozotocin to induce pre‐gestational diabetes, then mated with healthy males to produce offspring. They were also given access to running wheels 1 week before mating and allowed to exercise voluntarily until E18.5. Heart morphology, gene expression, and oxidative stress were assessed in foetal hearts. Maternal voluntary exercise results in a significantly lower incidence of CHDs from 59.5% to 25%. Additionally, diabetes‐induced defects in coronary artery and capillary morphogenesis were also lower with exercise. Myocardial cell proliferation and epithelial‐mesenchymal transition at E12.5 was significantly lower with pre‐gestational diabetes which was mitigated with maternal exercise. Cardiac gene expression of Notch1 , Snail1 , Gata4 and Cyclin D1 was significantly higher in the embryos of diabetic mice that exercised compared to the non‐exercised group. Furthermore, maternal exercise produced lower reactive oxygen species (ROS) and oxidative stress in the foetal heart. In conclusion, maternal exercise mitigates ROS and oxidative damage in the foetal heart, and results in a lower incidence of CHDs in the offspring of pre‐gestational diabetes. Exercise may be an effective intervention to compliment clinical management and further minimize CHD risk in mothers with diabetes.

Say NO to ROS: Their Roles in Embryonic Heart Development and Pathogenesis of Congenital Heart Defects in Maternal Diabetes

“…Activation and phosphorylation of eNOS-Ser1177 in the heart is mediated by Akt activation. As Akt activation has been shown to promote cardiomyocyte proliferation and expansion of cardiac progenitors [203], this pathway may also have contributed to protection against CHD pathogenesis observed in our model [16]. As of now, fetal adaptations in response to maternal exercise has not been well characterized.…”

“…Remarkably, maternal voluntary exercise for 3 months before conception has recently been shown to lower the incidence of VSDs in offspring of old mothers, suggesting maternal exercise reduces the risk of CHDs associated with maternal age [191]. Using a STZ diabetes mouse model, we examined the effects of maternal exercise on pathogenesis of CHDs induced by pregestational diabetes [16]. Our results show that maternal exercise reduces ROS levels and oxidative stress and improves eNOS phosphorylation in the fetal hearts of offspring from mice with diabetes.…”

“…This depletion of pancreatic β-cells and thereby insulin supply recapitulates T1D in humans. Animal studies analyzing heart development in this model of pregestational maternal diabetes indicate that reactive oxygen species (ROS) are critical players in mediating maladaptive heart development, leading to CHDs [13,14,15,16,17,18,19,20,21,22,23,24,25]. Oxidative stress, brought on by hyperglycemia, is not conducive to the development of cardiac progenitors as it results in the oxidation and inactivation of many molecules and enzymes necessary for cardiogenesis.…”

Cod-Liver Oil Improves Metabolic Indices and hs-CRP Levels in Gestational Diabetes Mellitus Patients: A Double-Blind Randomized Controlled Trial

“…An allocation concealment was performed to hide the method of sorting trial participants into treatment groups. Strict diet control was applied to all participants, as follows: (1) a diet plan based on the patient's basic condition [26]; (2) monitoring of blood glucose; (3) calculation of the daily calorie requirement according to the patient's weight and making of an individual-compliant dietary plan to control dietary uptake; (4) advocacy of small meals and optimization of the dietary structure to ensure a balanced energy supply; and (5) scientific and rational exercise [27]. After middle pregnancy, 550 patients were determined with GDM and evenly assigned into the intervention group (received 500 mg cod-liver oil in capsule form daily) and control group (received placebo).…”

Physical Activity During Pregnancy and After Delivery

“…In addition, the beneficial effect of physical activity was also proven using different in vivo animal models. So far, it was demonstrated that aerobic exercise decreased the production of reactive oxygen species (ROS) and oxidative stress in the fetal heart and minimized the risk of congenital heart defects via modulation of specific gene expression, in pre-gestational diabetes (Saiyin et al, 2019). Also, it is well known that physical activity leads to a decrease in glycemia, decreasing body weight and visceral adipose tissue and, at the same time, increasing insulin sensitivity.…”