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Jorgensen W, Gam C, Andersen JL, Schjerling P, Scheibye-Knudsen M, Mortensen OH, Grunnet N, Nielsen MO, Quistorff B. Changed mitochondrial function by pre- and/or postpartum diet alterations in sheep. Am J Physiol Endocrinol Metab 297: E1349-E1357, 2009. First published October 13, 2009; doi: 10.1152/ajpendo.00505.2009.--In a sheep model, we investigated diet effects on skeletal muscle mitochondria to look for fetal programming. During pregnancy, ewes were fed normally (N) or were 50% food restricted (L) during the last trimester, and lambs born to these ewes received a normal (N) or a high-fat diet (H) for the first 6 mo of life. We examined mitochondrial function in permeabilized muscle fibers from the lambs at 6 mo of age (adolescence) and after 24 mo of age (adulthood). The postpartum H diet for the lambs induced an ~30% increase (P < 0.05) of mitochondrial [MATHEMATICAL EXPRESSION NOT REPRODUCIBLE IN ASCII] and an ~50% increase (P < 0.05) of the respiratory coupling ratio (RCR) combined with lower levels of UCP3 and PGC-1[alpha] mRNA levels (P < 0.05). These effects proved to be reversible by a normal diet from 6 to 24 mo of age. However, at 24 too, a long-term effect of the maternal gestational diet restriction (fetal programming) became evident as a lower [MATHEMATICAL EXPRESSION NOT REPRODUCIBLE IN ASCII] (~40%, P < 0.05), a lower state 4 respiration (~40%, P < 0.05), and lower RCR (~15%, P < 0.05). Both PGC-l[alpha] and UCP3 mRNA levels were increased (P < 0.05). Two analyzed muscles were affected differently, and muscle rich in type I fibers was more susceptible to fetal programming. We conclude that fetal programming, seen as a reduced [MATHEMATICAL EXPRESSION NOT REPRODUCIBLE IN ASCII] in adulthood, results from gestational undernutrition. Postnatal high-fat diet results in a pronounced RCR and [MATHEMATICAL EXPRESSION NOT REPRODUCIBLE IN ASCII], increase in adolescence. However, these effects are reversible by diet correction and are not maintained in adulthood. metabolic syndrome; high-fat diet; nutrient restriction; maternal diet; respiratory coupling ratio doi: 10.1152/ajpendo.00505.2009

Peroxisome proliferator-activated receptor-[gamma] coactivator-1[alpha] and -1[beta] (PGC-1[alpha] and PGC-1[beta]) 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[alpha] and PGC-1[beta] 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[alpha] enhanced glycogen buildup twofold at 5 or 25 mM glucose, whereas PGC-1[beta] caused a decrease. Both PGC-1[alpha] and PGC-1[beta] 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[alpha] or PGC-1[beta] 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[beta] overexpression caused an increase in mRNA of the intermediary fast oxidative-associated MHC isoform MHCIIA. PGC-1[alpha] or PGC-1[beta] overexpression upregulated GLUT4 mRNA and downregulated myocyte enhancer factor 2C transcription factor mRNA; only PGC-1[alpha] overexpression caused an increase in the mRNA expression of TRB3, a negative regulator of insulin signaling. These results show that both PGC-1[alpha] and PGC-1[beta] 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 [gamma] coactivator-1; myosin heavy chain; enzyme activities; glycogen

Abstract Background Low 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. Results We 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. Conclusions Gestational 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 The mitochondrial pH gradient across the inner-membrane is stabilised by buffering of the matrix. A low-molecular mass buffer compound has to be localised in the matrix to maintain its alkaline pH value. Taurine is found ubiquitously in animal cells with concentrations in the millimolar range and its pKa value is determined to 9.0 (25°C) and 8.6 (37°C), respectively. Localisation of such a low-molecular buffer in the mitochondrial matrix, transforms the matrix into a biochemical reaction chamber for the important matrix-localised enzyme systems. Three acyl-CoA dehydrogenase enzymes, which are pivotal for beta-oxidation of fatty acids, are demonstrated to have optimal activity in a taurine buffer. By application of the model presented, taurine depletion caused by hyperglycemia could provide a link between mitochondrial dysfunction and diabetes.

Research was conducted to examine the regulation of glycogen accumulation in L6 myotubes cultured under optimized differentiation conditions. The objectives were to enhance the differentiation level of L6 cells, to identify conditions that stimulate glycogen accumulation and to examine the regulation of glycogen metabolism under conditions of optimized differentiation. Results indicate that factors other than phosphorylation and dephosphorylation play a significant role in the regulation of glycogen metabolism in L6 myotubes.

Abstract Background Using blood lactate monitoring for risk assessment in the critically ill patient remains controversial. Some of the discrepancy is due to uncertainty regarding the appropriate reference interval, and whether to perform a single lactate measurement as a screening method at admission to the hospital, or serial lactate measurements. Furthermore there is no consensus whether the sample should be drawn from arterial, peripheral venous, or capillary blood. The aim of this review was: 1) To examine whether blood lactate levels are predictive for in-hospital mortality in patients in the acute setting, i.e. patients assessed pre-hospitally, in the trauma centre, emergency department, or intensive care unit. 2) To examine the agreement between arterial, peripheral venous, and capillary blood lactate levels in patients in the acute setting. Methods We performed a systematic search using PubMed, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and CINAHL up to April 2011. 66 articles were considered potentially relevant and evaluated in full text, of these ultimately 33 articles were selected. Results and Conclusion The literature reviewed supported blood lactate monitoring as being useful for risk assessment in patients admitted acutely to hospital, and especially the trend, achieved by serial lactate sampling, is valuable in predicting in-hospital mortality. All patients with a lactate at admission above 2.5 mM should be closely monitored for signs of deterioration, but patients with even lower lactate levels should be considered for serial lactate monitoring. The correlation between lactate levels in arterial and venous blood was found to be acceptable, and venous sampling should therefore be encouraged, as the risk and inconvenience for this procedure is minimal for the patient. The relevance of lactate guided therapy has to be supported by more studies.