Department of Pediatrics, Section of Neonatology, Perinatal Research Center, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
Department of Medicine, Division of Endocrinology, Metabolism & Diabetes, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
J Physiol. 2024 Jun;602(12):2697-2715. doi: 10.1113/JP285496. Epub 2024 May 14.
Fetuses affected by intrauterine growth restriction have an increased risk of developing heart disease and failure in adulthood. Compared with controls, late gestation intrauterine growth-restricted (IUGR) fetal sheep have fewer binucleated cardiomyocytes, reflecting a more immature heart, which may reduce mitochondrial capacity to oxidize substrates. We hypothesized that the late gestation IUGR fetal heart has a lower capacity for mitochondrial oxidative phosphorylation. Left (LV) and right (RV) ventricles from IUGR and control (CON) fetal sheep at 90% gestation were harvested. Mitochondrial respiration (states 1-3, Leak, and maximal respiration) in response to carbohydrates and lipids, citrate synthase (CS) activity, protein expression levels of mitochondrial oxidative phosphorylation complexes (CI-CV), and mRNA expression levels of mitochondrial biosynthesis regulators were measured. The carbohydrate and lipid state 3 respiration rates were lower in IUGR than CON, and CS activity was lower in IUGR LV than CON LV. However, relative CII and CV protein levels were higher in IUGR than CON; CV expression level was higher in IUGR than CON. Genes involved in lipid metabolism had lower expression in IUGR than CON. In addition, the LV and RV demonstrated distinct differences in oxygen flux and gene expression levels, which were independent from CON and IUGR status. Low mitochondrial respiration and CS activity in the IUGR heart compared with CON are consistent with delayed cardiomyocyte maturation, and CII and CV protein expression levels may be upregulated to support ATP production. These insights will provide a better understanding of fetal heart development in an adverse in utero environment. KEY POINTS: Growth-restricted fetuses have a higher risk of developing and dying from cardiovascular diseases in adulthood. Mitochondria are the main supplier of energy for the heart. As the heart matures, the substrate preference of the mitochondria switches from carbohydrates to lipids. We used a sheep model of intrauterine growth restriction to study the capacity of the mitochondria in the heart to produce energy using either carbohydrate or lipid substrates by measuring how much oxygen was consumed. Our data show that the mitochondria respiration levels in the growth-restricted fetal heart were lower than in the normally growing fetuses, and the expression levels of genes involved in lipid metabolism were also lower. Differences between the right and left ventricles that are independent of the fetal growth restriction condition were identified. These results indicate an impaired metabolic maturation of the growth-restricted fetal heart associated with a decreased capacity to oxidize lipids postnatally.
受宫内生长受限影响的胎儿在成年后患心脏病和心力衰竭的风险增加。与对照组相比，晚期宫内生长受限（IUGR）胎儿羊的双核心肌细胞较少，反映出心脏更不成熟，这可能会降低线粒体氧化底物的能力。我们假设，晚期宫内生长受限胎儿心脏的线粒体氧化磷酸化能力较低。在妊娠 90%时，从宫内生长受限（IUGR）和对照（CON）胎儿羊的左（LV）和右（RV）心室中采集线粒体呼吸（状态 1-3、泄漏和最大呼吸），对碳水化合物和脂质的反应、柠檬酸合酶（CS）活性、线粒体氧化磷酸化复合物（CI-CV）的蛋白质表达水平以及线粒体生物合成调节剂的 mRNA 表达水平进行了测量。与 CON 相比，IUGR 的碳水化合物和脂质状态 3 呼吸速率较低，而 IUGR LV 的 CS 活性低于 CON LV。然而，IUGR 中的相对 CII 和 CV 蛋白水平高于 CON；CV 在 IUGR 中的表达水平高于 CON。与 CON 相比，IUGR 中参与脂质代谢的基因表达水平较低。此外，LV 和 RV 在氧通量和基因表达水平上表现出明显的差异，这些差异独立于 CON 和 IUGR 状态。与 CON 相比，IUGR 心脏中的线粒体呼吸和 CS 活性较低，这与心肌细胞成熟延迟一致，而 CII 和 CV 蛋白表达水平可能上调以支持 ATP 产生。这些发现将为在不良宫内环境中胎儿心脏发育提供更好的理解。 关键点：宫内生长受限的胎儿在成年后患心血管疾病和死亡的风险更高。 线粒体是心脏供应能量的主要来源。随着心脏的成熟，线粒体对底物的偏好从碳水化合物切换到脂质。我们使用绵羊宫内生长受限模型来研究使用碳水化合物或脂质底物产生能量的心脏中线粒体的产能能力，方法是测量消耗了多少氧气。我们的数据表明，生长受限胎儿心脏的线粒体呼吸水平低于正常生长的胎儿，参与脂质代谢的基因表达水平也较低。在独立于胎儿生长受限条件的左右心室之间也发现了差异。这些结果表明，与出生后氧化脂质的能力降低相关，生长受限胎儿心脏的代谢成熟受损。
