Diabetic Pregnancy and Maternal High-Fat Diet Impair Mitochondrial Dynamism in the Developing Fetal Rat Heart by Sex-Specific Mechanisms

International Journal of Molecular Sciences

Lothar Lauterboeck¹  KennedyS. Mdaki¹  MichelleL. Baack¹  EliJ. Louwagie¹  TriciaD. Larsen¹  TylerC. T. Gandy¹  AlexisJ. Knutson¹  KyleH. Sabey² 

[1] Environmental Influences on Health and Disease Group, Sanford Research, 2301 E 60th Street North, Sioux Falls, SD 57104, USA;Sanford School of Medicine of the University of South Dakota, Sioux Falls, SD 57117, USA;

关键词: maternal diabetes;    maternal high-fat diet;    cardiovascular disease;    mitochondrial dynamism;    sex-specific mechanisms of the developmental origins of health and disease (DOHaD);   

DOI  :  10.3390/ijms20123090

来源: DOAJ

【 摘 要 】

Infants born to diabetic or obese mothers are at greater risk of heart disease at birth and throughout life, but prevention is hindered because underlying mechanisms remain poorly understood. Using a rat model, we showed that prenatal exposure to maternal diabetes and a high-fat diet caused diastolic and systolic dysfunction, myocardial lipid accumulation, decreased respiratory capacity, and oxidative stress in newborn offspring hearts. This study aimed to determine whether mitochondrial dynamism played a role. Using confocal live-cell imaging, we examined mitochondrial dynamics in neonatal rat cardiomyocytes (NRCM) from four prenatally exposed groups: controls, diabetes, high-fat diet, and combination exposed. Cardiac expression of dynamism-related genes and proteins were compared, and gender-specific differences were evaluated. Findings show that normal NRCM have highly dynamic mitochondria with a well-balanced number of fusion and fission events. Prenatal exposure to diabetes or a high-fat diet impaired dynamism resulting in shorter, wider mitochondria. Mechanisms of impaired dynamism were gender-specific and protein regulated. Females had higher expression of fusion proteins which may confer a cardioprotective effect. Prenatally exposed male hearts had post-translational modifications known to impair dynamism and influence mitophagy-mediated cell death. This study identifies mitochondrial fusion and fission proteins as targetable, pathogenic regulators of heart health in offspring exposed to excess circulating maternal fuels.

【 授权许可】

Unknown