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Intrauterine growth retardation alters mitochondrial gene expression and function in fetal and juvenile rat skeletal
R H Lane1, A K Chandorkar, A S Flozak
1Department of Pediatrics, University of Pittsburgh School of Medicine, Magee-Women's Research Institute, Pennsylvania 15213, USA.
Insights
Uteroplacental insufficiency impacts fetal growth and alters skeletal muscle metabolism. Postnatal muscle mitochondrial gene expression and function are significantly changed in intrauterine growth retardation (IUGR) models.
Area of Science:
- Biochemistry
- Physiology
- Developmental Biology
Background:
- Uteroplacental insufficiency is a primary cause of intrauterine growth retardation (IUGR).
- IUGR leads to long-term metabolic and physiological consequences, including altered postnatal growth and glucose metabolism.
- Skeletal muscle plays a crucial role in growth and glucose metabolism, influenced by ATP availability.
Purpose of the Study:
- To investigate alterations in gene expression and function of mitochondrial proteins involved in ATP production and distribution in juvenile IUGR muscle.
- To determine if IUGR affects the mRNA levels of key mitochondrial proteins in fetal and juvenile rats.
- To assess the relationship between altered gene expression and mitochondrial function in IUGR muscle.
Main Methods:
- Utilized a rat model of IUGR induced by bilateral uterine artery ligation.
- Employed RT-PCR to quantify mRNA levels of NADH-ubiquinone-oxireductase subunit 4L (ND-4L), F1F0-ATP synthase subunit C (SUC), and adenine nucleotide translocator 1 (ANT1).
- Measured the mitochondrial NAD+/NADH ratio in juvenile IUGR and control muscle.
Main Results:
- Fetal IUGR muscle showed significantly increased mRNA levels for ND-4L, SUC, and ANT1.
- Juvenile IUGR muscle exhibited significantly decreased mRNA levels for ND-4L, SUC, and ANT1 compared to controls.
- Decreased gene expression in juvenile IUGR muscle correlated with a reduced mitochondrial NAD+/NADH ratio.
Conclusions:
- Uteroplacental insufficiency in rats induces significant changes in fetal and postnatal muscle mitochondrial mRNA expression.
- Postnatal mitochondrial function, indicated by the NAD+/NADH ratio, is altered in IUGR offspring.
- These findings highlight the lasting metabolic impact of IUGR on skeletal muscle mitochondrial biology.
Abstract:
Uteroplacental insufficiency alters the anabolic metabolism of the fetus, resulting in intrauterine growth retardation (IUGR). The metabolic and physiologic factors that cause IUGR have long standing consequences after birth. Postnatal growth and glucose metabolism are altered in the IUGR infant. Skeletal muscle is an important component of growth and metabolizes up to 70% of i.v. glucose. The ability of skeletal muscle to metabolize glucose is affected by ATP availability. We hypothesized that gene expression and function of proteins involved in mitochondrial ATP production and distribution would be altered in juvenile IUGR muscle. To test this hypothesis, we used a model of IUGR, induced by bilateral uterine artery ligation in the pregnant rat, that mimics uteroplacental insufficiency in the human. RT-PCR was used to measure the mRNA levels of three important mitochondrial proteins; NADH-ubiquinone-oxireductase subunit 4L(ND-4L), subunit C of the F1F0-ATP synthase (SUC), and adenine nucleotide translocator 1 (ANT1) in IUGR and control rats in fetal and juvenile life. In the fetus, mRNA levels of all three proteins were significantly increased in IUGR skeletal muscle. In contrast, in juvenile animals, mRNA levels of all three proteins were significantly decreased. mRNA levels of other metabolically important proteins, glucose-6-phosphate dehydrogenase and carnitine-palmitoyl-transferase II, were not significantly altered in IUGR juvenile animals. To assess if decreased gene expression is associated with altered mitochondrial function, we measured the mitochondrial NAD+/NADH ratio in d 21 juvenile control and IUGR muscle. At d 21, decreased gene expression if ND-4L, SUC, and ANTI is associated with a decreased mitochondrial NAD+/NADH ratio. The results of our study suggest that the metabolic alterations associated with uteroplacental insufficiency in the rat result in altered fetal and postnatal muscle mitochondrial mRNA expression as well as altered postnatal mitochondrial function.