Uteroplacental insufficiency and subsequent intrauterine growth retardation (IUGR) affects postnatal metabolism. In juvenile rats, IUGR alters skeletal muscle mitochondrial gene expression and reduces mitochondrial NAD ϩ /NADH ratios, both of which affect ␤-oxidation flux. We therefore hypothesized that gene expression and function of mitochondrial ␤-oxidation enzymes would be altered in juvenile IUGR skeletal muscle. To test this hypothesis, mRNA levels of five key mitochondrial enzymes (carnitine palmitoyltransferase I, trifunctional protein of ␤-oxidation, uncoupling protein-3, isocitrate dehydrogenase, and mitochondrial malate dehydrogenase) and intramuscular triglycerides were quantified in 21-d-old (preweaning) IUGR and control rat skeletal muscle. In isolated skeletal muscle mitochondria, enzyme function of the trifunctional protein of ␤-oxidation and isocitrate dehydrogenase were measured because both enzymes compete for mitochondrial NAD ϩ . Carnitine palmitoyltransferase I, the trifunctional protein of ␤-oxidation, and uncoupling protein 3 mRNA levels were significantly increased in IUGR skeletal muscle, whereas mRNA levels of isocitrate dehydrogenase and mitochondrial malate dehydrogenase were unchanged. Similarly, trifunctional protein of ␤-oxidation activity was increased in IUGR skeletal muscle mitochondria, and isocitrate dehydrogenase activity was unchanged. Interestingly, skeletal muscle triglycerides were significantly increased in IUGR skeletal muscle. We conclude that uteroplacental insufficiency alters IUGR skeletal muscle mitochondrial lipid metabolism, and we speculate that the changes observed in this study play a role in the long-term morbidity associated with IUGR. (Pediatr Res 50: 83-90, 2001) Abbreviations CPTI, carnitine palmitoyltransferase I IUGR, intrauterine growth retardation AGA, appropriate for gestational age ICD, isocitrate dehydrogenase MMD, mitochondrial malate dehydrogenase ND-4L, NADH-ubiquinone oxidoreductase subunit 4L HADH, trifunctional protein of ␤-oxidation HADHA, trifunctional protein of ␤-oxidation ␣ subunit UCP3, uncoupling protein 3 UCP3l, uncoupling protein 3-long isoform UCP3s, uncoupling protein 3-short isoform Uteroplacental insufficiency causes IUGR and is causally related to the development of multiple adult morbidities including insulin resistance, hypertension, coronary heart disease, and dyslipidemia (1). Although the effects of these pathophysiologies are most critically felt during adulthood, evidence exists that metabolism may already be altered in IUGR infants.Several investigators have demonstrated that IUGR infants expend more energy and consume more oxygen than AGA infants (2-6); moreover, Bohler et al.

Uteroplacental insufficiency causes intrauterine growth retardation (IUGR) and subsequent low birth weight, which predisposes the affected newborn towards adult Syndrome X. Individuals with Syndrome X suffer increased morbidity from adult ischemic heart disease. Myocardial ischemia initiates a defensive increase in cardiac glucose metabolism, and individuals with Syndrome X demonstrate reduced insulin sensitivity and reduced glucose uptake. Glucose transporters GLUT1 and GLUT4 facilitate glucose uptake across cardiac plasma membranes, and hexokinase II (HKII) is the predominant hexokinase isoform in adult cardiac tissue. We therefore hypothesized that GLUT1, GLUT4 and HKII gene expression would be reduced in heart muscle of growth-retarded rats, and that reduced gene expression would result in reduced myocardial glucose uptake. To prove this hypothesis, we measured cardiac GLUT1 and GLUT4 mRNA and protein in control IUGR rat hearts at day 21 and at day 120 of life. HKII mRNA quantification and 2-deoxyglucose-uptake studies were performed in day-120 control and IUGR cardiac muscle. Both GLUT1 and GLUT4 mRNA and protein were significantly reduced at day 21 and at day 120 of life in IUGR hearts. HKII mRNA was also reduced at day 120. Similarly, both basal and insulin-stimulated glucose uptake were significantly reduced in day-120 IUGR cardiac muscle. We conclude that adult rats showing IUGR as a result of uteroplacental insufficiency express significantly less cardiac GLUT1 and GLUT4 mRNA and protein than control animals (which underwent sham operations), and that this decrease in gene expression occurs in parallel with reduced myocardial glucose uptake. We speculate that this reduced GLUT gene expression and glucose uptake contribute towards mortality from ischemic heart disease seen in adults born with IUGR.