Diverse Effects of Intrauterine Growth Retardation (IUGR) upon Mitchondrial Gene Expression and Function in Male and Female d120 Soleus and Extensor Digitalis Longus (EDL) Muscle † 448

Uteroplacental insufficiency leading to IUGR is associated with an increased risk for adult dyslipidemia and insulin resistance. Fatty acid (FA) oxidation and insulin stimulated glucose uptake are key components of skeletal muscle metabolism. Skeletal muscle metabolism is also altered in rats rendered IUGR by maternal bilateral uterine artery ligation. Our lab has previously reported increased gene expression of L-3-Hydroxy-CoA Dehydrogenase (L3HD-the NAD dehydrogenase of beta oxidation),increased respiration from IUGR muscle mitochondria utilizing palmityl-carnitine, and decreased mitochondrial NAD/NADH ratio in d21 juvenile IUGR rat skeletal muscle. These findings favor FA oxidation over glucose oxidation (which is associated with insulin resistance) and suggest that competition for NAD plays a role in the regulation of mitochondrial oxidative metabolism. L3HD competes for NAD with the Kreb's cycle enzymes mitochondrial malate dehydrogenase(MMD) and isocitrate dehydrogenase(ICD). We therefore hypothesized that gene expression of L3HD,ICD,and MMD would be altered at d120 in soleus(oxidative) and EDL(glycolytic) muscle fibers in male and female rats. We performed bilateral uterine artery ligation and sham surgery (C). Animals were weighed, and RNA was isolated from EDL and soleus muscle at 120d. RT-PCR was performed using an internal control. At 120 days, IUGR males were significantly smaller than control (626±33gr versus 496±29;p < 0.05); however, there was no difference between IUGR (318±12 gr) and C (320±10) female rats. Results of RT-PCR are presented in the table below. Gene expression of L3HD was increased in all tissue except male EDL, and in contrast, gene expression of MMD and ICD were decreased in soleus and male EDL. We conclude that the altered metabolic milieu asociated with IUGR leads to altered gene expression of L3HD, MMD, and ICD in d120 IUGR skeletal muscle. The effects of the altered gene expression requires further study. We speculate that the differences in gene expression represent both a muscle fiber and gender specific response to the altered milieu associated with IUGR.

Table 1 No caption available.