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Altered expression and function of mitochondrial beta-oxidation enzymes in juvenile intrauterine-growth-retarded rat
R H Lane1, D E Kelley, V H Ritov
1Department of Pediatrics, UCLA School of Medicine, Mattel Children's Hospital at UCLA, Los Angeles, California 90095, USA. rlane@mednet.ucla.edu
Insights
Intrauterine growth retardation (IUGR) in juvenile rats alters skeletal muscle lipid metabolism. IUGR increases key beta-oxidation enzyme gene expression and activity, alongside higher triglyceride levels, impacting postnatal development.
Area of Science:
- Biochemistry
- Molecular Biology
- Developmental Biology
Background:
- Uteroplacental insufficiency leads to intrauterine growth retardation (IUGR), affecting postnatal metabolism.
- IUGR in juvenile rats is known to alter skeletal muscle mitochondrial gene expression and reduce NAD(+)/NADH ratios, impacting beta-oxidation.
- These metabolic changes suggest potential alterations in mitochondrial beta-oxidation enzymes.
Purpose of the Study:
- To investigate the gene expression and functional changes of mitochondrial beta-oxidation enzymes in the skeletal muscle of juvenile rats with IUGR.
- To quantify intramuscular triglyceride levels in IUGR and control rat skeletal muscle.
- To assess the activity of specific mitochondrial enzymes involved in NAD(+) competition.
Main Methods:
- Quantification of mRNA levels for five key mitochondrial enzymes: carnitine palmitoyltransferase I, trifunctional protein of beta-oxidation, uncoupling protein-3, isocitrate dehydrogenase, and mitochondrial malate dehydrogenase.
- Measurement of enzyme function for trifunctional protein of beta-oxidation and isocitrate dehydrogenase in isolated skeletal muscle mitochondria.
- Quantification of intramuscular triglycerides in 21-day-old IUGR and control rat skeletal muscle.
Main Results:
- Increased mRNA levels of carnitine palmitoyltransferase I, trifunctional protein of beta-oxidation, and uncoupling protein 3 in IUGR skeletal muscle.
- Unchanged mRNA levels for isocitrate dehydrogenase and mitochondrial malate dehydrogenase.
- Increased trifunctional protein of beta-oxidation activity and unchanged isocitrate dehydrogenase activity in IUGR skeletal muscle mitochondria.
- Significantly elevated intramuscular triglyceride levels in IUGR skeletal muscle.
Conclusions:
- Uteroplacental insufficiency significantly alters mitochondrial lipid metabolism in the skeletal muscle of IUGR rats.
- The observed changes in beta-oxidation enzyme expression and activity, along with increased triglycerides, suggest a role in the long-term metabolic consequences of IUGR.
- These findings highlight the impact of prenatal growth restriction on postnatal muscle metabolic programming.
Abstract:
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(+)/NADH ratios, both of which affect beta-oxidation flux. We therefore hypothesized that gene expression and function of mitochondrial beta-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 beta-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 beta-oxidation and isocitrate dehydrogenase were measured because both enzymes compete for mitochondrial NAD(+). Carnitine palmitoyltransferase I, the trifunctional protein of beta-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 beta-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.
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