Mortensen, Ole Hartvig, Lis Frandsen, Peter Schjerling, Erica Nishimura, and Niels Grunnet. PGC-1␣ and PGC-1␤ have both similar and distinct effects on myofiber switching toward an oxidative phenotype. Am J Physiol Endocrinol Metab 291: E807-E816, 2006. First published May 23, 2006 doi:10.1152/ajpendo.00591.2005.-Peroxisome proliferator-activated receptor-␥ coactivator-1␣ and -1␤ (PGC-1␣ and PGC-1␤) were overexpressed by adenovirus-mediated gene transfer in cultures of primary rat skeletal muscle cells derived from neonatal myoblasts. Effects on muscle fiber type transition and metabolism were studied from days 5 to 22 of culture. PGC-1␣ and PGC-1␤ overexpression caused a three-to fourfold increase in mRNA level, a doubling of enzymatic activity of citrate synthase, a slight increase in short-chain acyl-CoA dehydrogenase mRNA, a doubling of the mRNA level, and a 30 -50% increase in enzymatic activity of glyceraldehyde-3-phosphate dehydrogenase. Lactate dehydrogenase or creatine kinase activity was unchanged. PGC-1␣ enhanced glycogen buildup twofold at 5 or 25 mM glucose, whereas PGC-1␤ caused a decrease. Both PGC-1␣ and PGC-1␤ overexpression caused a faster maturation of myotubes, as seen by mRNA downregulation of the immature embryonal and perinatal myosin heavy-chain (MHC) isoforms. PGC-1␣ or PGC-1␤ overexpression enhanced mRNA of the slow oxidative-associated MHC isoform MHCIb and downregulated mRNA levels of the fast glycolytic-associated MHC isoforms MHCIIX and MHCIIB. Only PGC-1␤ overexpression caused an increase in mRNA of the intermediary fast oxidative-associated MHC isoform MHCIIA. PGC-1␣ or PGC-1␤ overexpression upregulated GLUT4 mRNA and downregulated myocyte enhancer factor 2C transcription factor mRNA; only PGC-1␣ overexpression caused an increase in the mRNA expression of TRB3, a negative regulator of insulin signaling. These results show that both PGC-1␣ and PGC-1␤ are involved in the regulation of skeletal muscle fiber transition and metabolism and that they have both overlapping and differing effects. skeletal muscle cell culture; peroxisome proliferator-activated receptor ␥ coactivator-1; myosin heavy chain; enzyme activities; glycogen THE BENEFICIAL EFFECT of exercise on various diseases is widely acknowledged (7), and exercise has proven particularly successful as a treatment for the metabolic syndrome, including type 2 diabetes (48); however, the exact molecular pathway responsible for the effect is largely unknown. Recently, genes involved in oxidative phosphorylation in skeletal muscle were found to be downregulated in patients with type 2 diabetes (37, 43), and speculations about type 2 diabetes being caused by mitochondrial dysfunction, primarily in the type I skeletal muscle fibers, have surfaced (13,31,51). Regular exercise has been shown to induce changes in both skeletal muscle metabolism and muscle fiber type over time, most notably an increase in mitochondrial content and oxidative metabolism as well as a shift toward a more slow oxidative fiber type (8,44).

BackgroundLow birth weight is associated with an increased risk of developing impaired glucose tolerance, and eventually type 2 diabetes in adult life. Gestational protein restriction in rodents gives rise to a low birth weight phenotype in the offspring.ResultsWe examined gene expression changes in liver and skeletal muscle of mice subjected to gestational protein restriction (LP) or not (NP), with or without taurine supplementation in the drinking water. LP offspring had a 40% lower birth weight than NP offspring, with taurine preventing half the decrease. Microarray gene expression analysis of newborn mice revealed significant changes in 2012 genes in liver and 967 genes in skeletal muscle of LP offspring. Taurine prevented 30% and 46% of these expression changes, respectively. Mitochondrial genes, especially those involved with oxidative phosphorylation, were more abundantly changed than other genes. The mitochondrial genes were mainly upregulated in liver, but downregulated in skeletal muscle, despite no change in citrate synthase activity in either tissue. Taurine preferentially rescued genes concerned with fatty acid metabolism in liver and with oxidative phosphorylation and TCA cycle in skeletal muscle. A mitochondrial signature was seen in the liver of NP offspring with taurine supplementation, as gene sets for mitochondrial ribosome as well as lipid metabolism were over represented in 4-week-old offspring subjected to gestational taurine supplementation. Likewise, 11 mitochondrial genes were significantly upregulated by gestational taurine supplementation in 4-week-old NP offspring.ConclusionsGestational protein restriction resulted in lower birth weight associated with significant gene expression changes, which was different in liver and muscle of offspring. However, a major part of the birth weight decrease and the expression changes were prevented by maternal taurine supplementation, implying taurine is a key factor in determining expression patterns during development and in that respect also an important component in metabolic fetal programming.

ABSTRACT:We examined gene expression changes in liver and skeletal muscle of newborn mice subjected to a maternal low protein (LP) or normal protein (NP) diet during pregnancy, with or without taurine supplementation in the drinking water. LP offspring had a 40% lower birthweight than NP offspring, whereas it was reduced by only 20% with taurine supplementation. Microarray gene expression analysis revealed significant changes in 2012 genes in liver and 967 genes in skeletal muscle of LP offspring. By unknown mechanisms, taurine partially or fully prevented 30 and 46% of these expression changes, respectively. Mitochondrial genes, in particular genes associated with oxidative phosphorylation, were more abundantly changed in LP offspring, with primarily up-regulation in liver but down-regulation in skeletal muscle. In both tissues, citrate synthase activity remained unchanged. Taurine preferentially rescued changes in genes concerned with fatty acid metabolism in liver and with oxidative phoshorylation and tri carboxylic acid (TCA) cycle in skeletal muscle. Conclusion: Gestational protein restriction resulted in lower birthweight associated with significant gene expression changes, which was different in liver and muscle of offspring. However, a major part of the birthweight decrease and the expression changes were prevented by maternal taurine supplementation, implying taurine is a key component in metabolic fetal programming. (Pediatr Res 67: 47-53, 2010)

Extreme diets consisting of either high fat (HF) or high sucrose (HS) may lead to insulin resistance in skeletal muscle, often associated with mitochondrial dysfunction. However, it is not known if these diets alter normal interactions of pyruvate and fatty acid oxidation at the level of the mitochondria. Here, we report that rat muscle mitochondria does show the normal Randle‐type fat‐carbohydrate interaction seen in vivo. The mechanism behind this metabolic flexibility at the level of the isolated mitochondria is a regulation of the flux‐ratio: pyruvate dehydrogenase (PDH)/β‐oxidation to suit the actual substrate availability, with the PDH flux as the major point of regulation. We further report that this regulatory mechanism of carbohydrate‐fat metabolic interaction surprisingly is lost in mitochondria obtained from animals exposed for 12 weeks to a HF‐ or a HS diet as compared to rats given a normal chow diet. The mechanism seems to be a loss of the PDH flux decrease seen in controls, when fatty acid is supplied as substrate in addition to pyruvate, and vice versa for the supply of pyruvate as substrate to mitochondria oxidizing fatty acid. Finally, we report that the calculated TCA flux in the isolated mitochondria under these circumstances shows a significant reduction (~50%) after the HF diet and an even larger reduction (~75%) after the HS diet, compared with the chow group. Thus, it appears that obesogenic diets as those applied here have major influence on key metabolic performance of skeletal muscle mitochondria.

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