Characterizing Early Cardiac Metabolic Programming via 30% Maternal Nutrient Reduction during Fetal Development in a
Susana P Pereira1,2,3,4, Mariana S Diniz2,5, Ludgero C Tavares2,6
1Laboratory of Metabolism and Exercise (LaMetEx), Research Centre in Physical Activity, Health and Leisure (CIAFEL), Laboratory for Integrative and Translational Research in Population Health (ITR), Faculty of Sports, University of Porto, 4200-450 Porto, Portugal.
Insights
Maternal nutrition restriction during pregnancy causes early fetal heart changes. These sex-specific mitochondrial adaptations in fetuses may increase cardiovascular disease risk later in life.
Area of Science:
- Reproductive Biology
- Developmental Biology
- Mitochondrial Biology
Background:
- Intra-uterine growth restriction (IUGR) is a significant cause of fetal and neonatal complications.
- IUGR is linked to an increased risk of cardiovascular disease (CVD) in offspring.
- Mitochondria are crucial for cardiac function, and their programming may be affected by IUGR.
Purpose of the Study:
- To investigate early in utero fetal cardiac mitochondrial programming in response to IUGR.
- To determine if IUGR-induced mitochondrial adaptations are detectable at an early gestational stage.
- To explore potential sex-divergent responses in fetal cardiac mitochondria to IUGR.
Main Methods:
- Utilized a nonhuman primate model to induce IUGR via maternal nutritional restriction (30% diet reduction).
- Collected fetal cardiac left ventricle (LV) tissue and blood at 90 days of gestation (0.5 G).
- Assessed blood biochemical parameters and evaluated LV mitochondrial biology, including gene and protein expression of oxidative phosphorylation (OXPHOS) subunits.
Main Results:
- Maternal nutritional restriction led to detectable biochemical changes in fetal blood, indicating an early response.
- In utero cardiac mitochondrial adaptations were observed in a sex-divergent manner.
- IUGR induced alterations in cardiac gene expression of OXPHOS subunits and increased protein content for specific complexes in male fetuses, but not females.
Conclusions:
- Early IUGR, induced by maternal nutritional restriction, results in detectable fetal blood adaptations and sex-specific changes in cardiac mitochondrial gene and protein expression.
- These early mitochondrial adaptations, particularly affecting OXPHOS, suggest a role in the offspring's predisposition to CVD.
- The findings highlight a sex-specific fetal cardiac response to IUGR, potentially influencing long-term cardiovascular health outcomes.
Abstract:
Intra-uterine growth restriction (IUGR) is a common cause of fetal/neonatal morbidity and mortality and is associated with increased offspring predisposition for cardiovascular disease (CVD) development. Mitochondria are essential organelles in maintaining cardiac function, and thus, fetal cardiac mitochondria could be responsive to the IUGR environment. In this study, we investigated whether in utero fetal cardiac mitochondrial programming can be detectable in an early stage of IUGR pregnancy. Using a well-established nonhuman IUGR primate model, we induced IUGR by reducing by 30% the maternal diet (MNR), both in males (MNR-M) and in female (MNR-F) fetuses. Fetal cardiac left ventricle (LV) tissue and blood were collected at 90 days of gestation (0.5 gestation, 0.5 G). Blood biochemical parameters were determined and heart LV mitochondrial biology assessed. MNR fetus biochemical blood parameters confirm an early fetal response to MNR. In addition, we show that in utero cardiac mitochondrial MNR adaptations are already detectable at this early stage, in a sex-divergent way. MNR induced alterations in the cardiac gene expression of oxidative phosphorylation (OXPHOS) subunits (mostly for complex-I, III, and ATP synthase), along with increased protein content for complex-I, -III, and -IV subunits only for MNR-M in comparison with male controls, highlight the fetal cardiac sex-divergent response to MNR. At this fetal stage, no major alterations were detected in mitochondrial DNA copy number nor markers for oxidative stress. This study shows that in 90-day nonhuman primate fetuses, a 30% decrease in maternal nutrition generated early in utero adaptations in fetal blood biochemical parameters and sex-specific alterations in cardiac left ventricle gene and protein expression profiles, affecting predominantly OXPHOS subunits. Since the OXPHOS system is determinant for energy production in mitochondria, our findings suggest that these early IUGR-induced mitochondrial adaptations play a role in offspring's mitochondrial dysfunction and can increase predisposition to CVD in a sex-specific way.
