IUGR Alters Postnatal Rat Skeletal Muscle Peroxisome Proliferator-Activated Receptor-γ Coactivator-1 Gene Expression in a Fiber Specific Manner

Abstract

Uteroplacental insufficiency and subsequent intrauterine growth retardation (IUGR) increase the risk of insulin resistance in humans and rats. Aberrant skeletal muscle lipid metabolism contributes to the pathogenesis of insulin resistance. Peroxisome proliferator-activated receptor-␥ co-activator-1 (PGC-1) is a transcriptional co-activator that affects gene expression of key lipid metabolizing enzymes such as carnitine palmitoyltransferase I (mCPTI). Because gene expression of lipid metabolizing enzymes is altered in IUGR postnatal skeletal muscle, and we hypothesized that PGC-1 expression would be similarly affected. To prove this hypothesis, bilateral uterine artery ligation and sham surgery were used to produce IUGR and control rats respectively. Western Blotting demonstrated that PGC-1 hind limb skeletal muscle protein levels were increased in perinatal and postnatal IUGR rats. Conventional RT-PCR demonstrated that PGC-1 mRNA levels were similarly increased in perinatal hind limb skeletal muscle and juvenile extensor digitorum longus (EDL), but were decreased in juvenile soleus. Because a gender specific trend was noted in PGC-1 mRNA levels, real time RT-PCR was used for further differentiation. Real time RT-PCR revealed that changes in postnatal skeletal muscle PGC-1 expression were more marked in male IUGR rats versus female IUGR rats. Down stream targets of PGC-1 followed a similar pattern of expression. We conclude that PGC-1 expression is altered in rat IUGR skeletal muscle and speculate that it contributes to the pathogenesis of insulin resistance in the IUGR rat. Barker's Fetal Origins of Adult Disease Hypothesis proposes that fetal adaptation to a deprived intrauterine milieu leads to permanent changes in cellular biology and systemic physiology (1). Intrauterine growth retardation (IUGR) predisposes affected newborns toward the development of insulin resistance and dyslipidemia (2). Although both insulin deficiency and resistance contribute to the IUGR diabetic phenotype, asymmetrical IUGR individuals are often characterized by insulin resistance. Uteroplacental insufficiency, a morbidity associated with many common complications of pregnancy induces asymmetrical IUGR (3, 4). In the rat, uteroplacental insufficiency results in juvenile IUGR animals whose glucose homeostasis is abnormal only when physiologically challenged on a pharmacological level (5). By adulthood, these IUGR rats develop overt diabetes that is characterized by insulin resistance and hypertriglyceridemia (5,19,20).An important component contributing to the pathogenesis of skeletal muscle insulin resistance is altered fatty acid homeostasis (6, 7

Uteroplacental insufficiency and reducing litter size alters skeletal muscle mitochondrial biogenesis in a sex-specific manner in the adult rat

“…In previous studies examining these in the rat, control litters were typically culled to reduce the litter size to that of uteroplacental-insufficient litters (12,13,29). We have now shown, however, that reductions in litter size have an adverse impact on mammary function and on postnatal growth of the offspring (20) and may itself independently program later adverse outcomes.…”

“…This restriction of prenatal and postnatal substrate induces insulin resistance, impaired glucose tolerance, and subsequently diabetes in adult offspring (29,30). However, the impact of uteroplacental insufficiency on skeletal muscle lipid accumulation and mitochondrial biogenesis and how this relates to changes in adult insulin action in animal models is limited and equivocal (12,13,29). Uteroplacental insufficiency increases skeletal muscle triglycerides in the juvenile rat, but this coincides with elevated enzyme activity and mRNA levels of several mitochondrial ␤-oxidation enzymes, consistent with increased fatty acid oxidation (12).…”

“…Uteroplacental insufficiency increases skeletal muscle triglycerides in the juvenile rat, but this coincides with elevated enzyme activity and mRNA levels of several mitochondrial ␤-oxidation enzymes, consistent with increased fatty acid oxidation (12). Furthermore, uteroplacental insufficiency increases the protein expression of a major regulator of mitochondrial biogenesis, peroxisome proliferator-activated receptor (PPAR)␥ coactivator-1␣ (PCG-1␣) in hindlimb skeletal muscle from juvenile rats (13). This suggests improved mitochondrial biogenesis and fatty acid oxidation, inconsistent with elevated triglycerides and later onset of insulin resistance.…”

“…To minimize stress associated with metabolic assessment in vivo, animals were chronically catheterized. Furthermore, male and female offspring were studied separately, as marked sex differences in a range of outcomes following uteroplacental insufficiency and other challenges have been reported, notably in insulin action and glucose tolerance and their molecular determinants (13,21). On the basis of the association between reduced mitochondrial biogenesis, lipid accumulation, and insulin resistance in skeletal muscle (11,17,18,23,26), we hypothesized that mitochondrial biogenesis markers [i.e., PGC-1␣, mitochondrial transcription factor A (mtTFA) and cytochrome oxidase (COX)] would be reduced, and triglyceride levels increased, in the skeletal muscle of adult (6-mo-old) rats that were exposed to uteroplacental insufficiency.…”

Impact of selected inborn errors of metabolism on prenatal and neonatal development

“…In rats with intrauterine growth retardation, altered expression of the peroxisome proliferator-activated receptor gamma coactivator-1 (PGC-1), which is an important regulator of fatty acid metabolism, was shown (67). There are indications that regulation of fatty acid oxidation activity during fetal development might not only be important for fetal life.…”