Kegg Pathway: Pyruvate metabolism

Toxicol In Vitro. 2009 Nov 16;
Lepper TW, Oliveira E, Koch GD, Berlese DB, Feksa LR

Lead intoxication is a serious occupational disease that constitutes a major public health problem. Lead, a heavy metal, has been used by humans for many technological purposes, which is the main reason for its widespread distribution. The toxic mechanisms of lead on the molecular machinery of living organisms include metal transport, energy metabolism, diverse enzymatic processes, genetic regulation, and membrane ionic channels and signaling molecules. Since lead is able to cross the blood-brain barrier it may cause neurotoxicity. Creatine kinase and Pyruvate kinase are two thiol-containing enzymes that exert a key role for cellular energy homeostasis in brain. Our main objective was to investigate the in vitro effect of lead on Pyruvate kinase and creatine kinase activities of extracts and subcellular fractions from the brain cortex of rats in the presence or not of thiol-protecting substances such as glutathione and cysteamine. The results showed that lead inhibited the two enzyme activities and the thiol-protecting substances prevented their inhibition. These results suggest that lead inhibits creatine kinase and Pyruvate kinase activity by interaction with their thiol groups. Therefore, lead may disrupt energy homeostasis and this effect may contribute to the neurological dysfunction found in lead exposed individuals.

Cancer Biol Ther. 2010 Feb 21; 9(2):
Yang D, Wang MT, Tang Y, Chen Y, Jiang H, Jones TT, Rao K, Brewer GJ, Singh KK, Nie D

A common metabolic change in cancer is the acquisition of glycolytic phenotypes. Increased expression of glycolytic enzymes is considered as one contributing factor. The role of mitochondrial defects in acquisition of glycolytic phenotypes has been postulated but remains controversial. Here we show that functional defects in mitochondrial respiration could be induced by oncogenic H-Ras(Q61L) transformation, even though the mitochondrial contents or mass was not reduced in the transformed cells. First, mitochondrial respiration, as measured by mitochondrial oxygen consumption, was suppressed in NIH-3T3 cells transformed with H-Ras(Q61L). Second, oligomycin or rotenone did not reduce the cellular ATP levels in the H-Ras(Q61L) transformed cells, suggesting a diminished role of mitochondrial respiration in the cellular energy metabolism. Third, inhibition of glycolysis with iodoacetic acid reduced ATP levels at a much faster rate in H-Ras(Q61L) transformed cells than in the vector control cells. The reduction of cellular ATP levels was reversed by exogenously added Pyruvate in the vector control cells but not in H-Ras(Q61L) transformed cells. Finally when compared to the HRas(Q61L) transformed cells, the vector control cells had increased resistance toward glucose deprivation. The increased resistance was dependent on mitochondrial oxidative phosphorylation since rotenone or oligomycin abolished the increased survival of the vector control cells under glucose deprivation. The results also suggest an inability of the H-Ras(Q61L) transformed cells to reactivate mitochondrial respiration under glucose deprivation. Taken together, the data suggest that mitochondrial respiration can be impaired during transformation of NIH-3T3 cells by oncogeneic H-Ras(Q61L).

Cell Cycle. 2009 Dec 5; 8(23):
Pavlides S, Whitaker-Menezes D, Castello-Cros R, Flomenberg N, Witkiewicz AK, Frank PG, Casimiro MC, Wang C, Fortina P, Addya S, Pestell RG, Martinez-Outschoorn UE, Sotgia F, Lisanti MP

Here, we propose a new model for understanding the Warburg effect in tumor metabolism. Our hypothesis is that epithelial cancer cells induce the Warburg effect (aerobic glycolysis) in neighboring stromal fibroblasts. These cancer-associated fibroblasts, then undergo myo-fibroblastic differentiation, and secrete lactate and Pyruvate (energy metabolites resulting from aerobic glycolysis). Epithelial cancer cells could then take up these energy-rich metabolites and use them in the mitochondrial TCA cycle, thereby promoting efficient energy production (ATP generation via oxidative phosphorylation), resulting in a higher proliferative capacity. In this alternative model of tumorigenesis, the epithelial cancer cells instruct the normal stroma to transform into a wound-healing stroma, providing the necessary energy-rich micro-environment for facilitating tumor growth and angiogenesis. In essence, the fibroblastic tumor stroma would directly feed the epithelial cancer cells, in a type of host-parasite relationship. We have termed this new idea the "Reverse Warburg Effect." In this scenario, the epithelial tumor cells "corrupt" the normal stroma, turning it into a factory for the production of energy-rich metabolites. This alternative model is still consistent with Warburg's original observation that tumors show a metabolic shift towards aerobic glycolysis. In support of this idea, unbiased proteomic analysis and transcriptional profiling of a new model of cancer-associated fibroblasts (caveolin-1 (Cav-1) deficient stromal cells), shows the upregulation of both (1) myo-fibroblast markers and (2) glycolytic enzymes, under normoxic conditions. We validated the expression of these proteins in the fibroblastic stroma of human breast cancer tissues that lack stromal Cav-1. Importantly, a loss of stromal Cav-1 in human breast cancers is associated with tumor recurrence, metastasis, and poor clinical outcome. Thus, an absence of stromal Cav-1 may be a biomarker for the "Reverse Warburg Effect," explaining its powerful predictive value.

J Membr Biol. 2009 Nov 17;
Modi HR, Katyare SS

Effects of treatment with a single intraperitoneal injection of cadmium (Cd) on oxidative energy metabolism and lipid/phospholipid profiles of rat liver mitochondria were examined at the end of 1 week and 1 month. Following Cd treatment the body weight increased only in the 1 month group, whereas the liver weight increased in both groups. State 3 and 4 respiration rates in general decreased significantly, with the maximum effect being seen with succinate. The 1 week Cd group showed decreased respiratory activity with glutamate, Pyruvate + malate, and succinate as the substrates. In the 1 month Cd-treated group respiration rates recovered with glutamate and Pyruvate + malate but not with succinate. All cytochrome contents decreased in the 1 week Cd-treated group but recovered in the 1 month group. ATPase activity registered an increase in both Cd-treated groups. Dehydrogenase activities increased in the 1 week group but decreased in the 1 month Cd-treated group. The mitochondrial cholesterol content increased in the 1 week Cd-treated group. In the 1 week Cd-treated group the lysophospholipid (Lyso), sphingomyelin (SPM), and diphosphatidylglycerol (DPG) components increased. By contrast, the phosphatidylethanolamine (PE) component decreased. In the 1 month Cd-treated group the phosphatidylinositol, phosphatidylserine, and DPG components increased, whereas the Lyso, SPM, and phosphatidylcholine components decreased. The results demonstrate that single-dose Cd treatment can have adverse effects on liver mitochondrial oxidative energy metabolism and lipid/phosphopholipid profiles, which in turn can affect membrane structure-function relationships.

J Cardiovasc Pharmacol. 2009 Nov 13;
Zhang J, Chatterjee K, Alano CC, Kalinowski MA, Ma NH, Karliner JS

The DNA-damaging agent N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) causes cardiomyocyte death due to energy loss from excessive activation of poly-(ADP) ribose polymerase-1 (PARP-1) resulting in depletion of its substrates nicotinamide adenine dinucleotide (NAD) and ATP. Previously we showed that the chemotherapeutic agent vincristine (VCR) is cardioprotective. Here we tested the hypothesis that VCR inhibits MNNG-induced PARP activation. Adult mouse cardiomyocytes were incubated with 100 mumol/L MNNG with or without concurrent VCR (20 mumo/L) for 2-4 hours. Cardiomyocyte survival was measured using the trypan blue exclusion assay. Western blots were employed to measure signaling responses. MNNG induced-cardiomyocyte damage was time and concentration dependent. MNNG activated PARP-1 and depleted NAD and ATP. VCR completely protected cardiomyocytes from MNNG -induced cell damage and maintained intracellular levels of NAD and ATP. VCR increased phosphorylation of the prosurvival signals Akt, GSK-3beta, Erk1/2, and p70S6 kinase. VCR delayed PARP activation as evidenced by western blot and by immunofluorescence staining of poly (ADP)-ribose, but without directly inhibiting PARP-1 itself. Known PARP-1 inhibitors also protected cardiomyocytes from MNNG- induced death. Repletion of ATP, NAD, Pyruvate and glutamine had effects similar to PARP-1 inhibitors. We conclude that VCR protects cardiomyocytes from MNNG toxicity by regulating PARP-1 activation, intracellular energy metabolism and prosurvival signaling.

Sci Signal. 2009; 2(97): ra73
Hitosugi T, Kang S, Vander Heiden MG, Chung TW, Elf S, Lythgoe K, Dong S, Lonial S, Wang X, Chen GZ, Xie J, Gu TL, Polakiewicz RD, Roesel JL, Boggon TJ, Khuri FR, Gilliland DG, Cantley LC, Kaufman J, Chen J

The Warburg effect describes a pro-oncogenic metabolism switch such that cancer cells take up more glucose than normal tissue and favor incomplete oxidation of glucose even in the presence of oxygen. To better understand how tyrosine kinase signaling, which is commonly increased in tumors, regulates the Warburg effect, we performed phosphoproteomic studies. We found that oncogenic forms of fibroblast growth factor receptor type 1 inhibit the Pyruvate kinase M2 (PKM2) isoform by direct phosphorylation of PKM2 tyrosine residue 105 (Y(105)). This inhibits the formation of active, tetrameric PKM2 by disrupting binding of the PKM2 cofactor fructose-1,6-bisphosphate. Furthermore, we found that phosphorylation of PKM2 Y(105) is common in human cancers. The presence of a PKM2 mutant in which phenylalanine is substituted for Y(105) (Y105F) in cancer cells leads to decreased cell proliferation under hypoxic conditions, increased oxidative phosphorylation with reduced lactate production, and reduced tumor growth in xenografts in nude mice. Our findings suggest that tyrosine phosphorylation regulates PKM2 to provide a metabolic advantage to tumor cells, thereby promoting tumor growth.

Sci Signal. 2009; 2(97): pe75
Dang CV

New evidence suggests that the receptor tyrosine kinase FGFR1 (fibroblast growth factor receptor 1) directly phosphorylates Pyruvate kinase M2 (PKM2), resulting in reduced conversion of phosphoenolPyruvate to Pyruvate, which is further catabolized to lactate by lactate dehydrogenase A. Mutation of the critical tyrosine Tyr(105) to Phe rendered PKM2 more active but was associated with decreased cellular lactate production, increased oxygen consumption, and decreased hypoxic cell proliferation relative to wild-type PKM2. The apparent paradoxical effect of growth signaling through tyrosine phosphorylation, which decreases rather than increases PKM2 activity, stimulates a revised perspective of the Warburg effect. This effect, which describes the propensity for cancer cells to convert glucose to lactate at a high rate, must now accommodate links among glycolysis, the tricarboxylic acid cycle, and glutamine metabolism in cancer cells.

Proc Natl Acad Sci U S A. 2009 Nov 16;
Zhang X, Jantama K, Moore JC, Jarboe LR, Shanmugam KT, Ingram LO

During metabolic evolution to improve succinate production in Escherichia coli strains, significant changes in cellular metabolism were acquired that increased energy efficiency in two respects. The energy-conserving phosphoenolPyruvate (PEP) carboxykinase (pck), which normally functions in the reverse direction (gluconeogenesis; glucose repressed) during the oxidative metabolism of organic acids, evolved to become the major carboxylation pathway for succinate production. Both PCK enzyme activity and gene expression levels increased significantly in two stages because of several mutations during the metabolic evolution process. High-level expression of this enzyme-dominated CO(2) fixation and increased ATP yield (1 ATP per oxaloacetate). In addition, the native PEP-dependent phosphotransferase system for glucose uptake was inactivated by a mutation in ptsI. This glucose transport function was replaced by increased expression of the GalP permease (galP) and glucokinase (glk). Results of deleting individual transport genes confirmed that GalP served as the dominant glucose transporter in evolved strains. Using this alternative transport system would increase the pool of PEP available for redox balance. This change would also increase energy efficiency by eliminating the need to produce additional PEP from Pyruvate, a reaction that requires two ATP equivalents. Together, these changes converted the wild-type E. coli fermentation pathway for succinate into a functional equivalent of the native pathway that nature evolved in succinate-producing rumen bacteria.

J Mol Med. 2009 Nov 14;
Wang W, Wong CW

Peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha) serves as an inducible coactivator for a number of transcription factors to control energy metabolism. Insulin signaling through Akt kinase has been demonstrated to phosphorylate PGC-1alpha at serine 571 and downregulate its activity in the liver. Statins are 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors that reduce cholesterol synthesis in the liver. In this study, we found that statins reduced the active form of Akt and enhanced PGC-1alpha activity. Specifically, statins failed to activate an S571A mutant of PGC-1alpha. The activation of PGC-1alpha by statins selectively enhanced the expression of energy metabolizing enzymes and regulators including peroxisome proliferator-activated receptor alpha, acyl-CoA oxidase, carnitine palmitoyl transferase-1A, and Pyruvate dehydrogenase kinase 4. Importantly, a constitutively active form of Akt partially reduced the statin-enhanced gene expression. Our study thus provides a plausible mechanistic explanation for the hypolipidemic effect of statin through elevating the rate of beta-oxidation and mitochondrial Kreb's cycle capacity to enhance fatty acid utilization while reducing the rate of glycolysis.

Med Sci Sports Exerc. 2009 Dec; 41(12): 2136-2144
Wang L, Psilander N, Tonkonogi M, Ding S, Sahlin K

PURPOSE:: There is a debate whether interval or traditional endurance training is the most effective stimulus of mitochondrial biogenesis. Here, we compared the effects of acute interval exercise (IE) or continuous exercise (CE) on the muscle messenger RNA (mRNA) content for several genes involved in mitochondrial biogenesis and lipid metabolism. METHODS:: Nine sedentary subjects cycled for 90 min with two protocols: CE (at 67% V O2max) and IE (12 s at 120% and 18 s at 20% of V O2max). The duration of exercise and work performed with CE and IE was identical. Muscle biopsies were taken before and 3 h after exercise. RESULTS:: There were no significant differences between the two exercise protocols in the increases in V O2 and HR, the reduction in muscle glycogen (35%-40% with both protocols) or the changes in blood metabolites (lactate, glucose, and fatty acids). The mRNA content for major regulators of mitochondrial biogenesis [peroxisome proliferator-activated receptor (PPAR) gamma coactivator 1alpha (PGC-1alpha), PGC-1-related coactivator, PPAR/delta] and of lipid metabolism [Pyruvate dehydrogenase kinase isozyme 4 (PDK4)] increased after exercise, but there was no significant difference between IE and CE. However, the mRNA content for several downstream targets of PGC-1alpha increased significantly only after CE, and mRNA content for nuclear respiratory factor 2 was significantly higher after CE (P < 0.025 vs IE). CONCLUSIONS:: The present findings demonstrate that, when the duration of exercise and work performed is the same, IE and CE influence the transcription of genes involved in oxidative metabolism in a similar manner.

J Chromatogr A. 2009 Oct 31;
Chuang CK, Wang TJ, Yeung CY, Lin DS, Lin HY, Liu HL, Ho HT, Hsieh WS, Lin SP

Lactic acidemia is commonly associated with severe diseases in pediatric patients. Quantitation of blood lactate and Pyruvate is important for the diagnosis and clinical management. A liquid chromatography-tandem mass spectrometry (LC-MS/MS) method using dried blood spots (DBS) was developed and could be used for simultaneous quantification of blood lactate and Pyruvate. The applicability of the developed method was tested and confirmed by the regression analysis between LC-MS/MS method and enzymatic assay. Lactate and Pyruvate were extracted from DBS obtained from 580 full-term, 120 pre-term infants (gestations ranging from 24 to 36 weeks), and 65 patients with suspected lactic acidemia, with methanolic internal standard (IS) solutions of sodium l-lactate-(13)C(3) and Pyruvate-(13)C(3). An API-2000 LC-MS/MS system with multiple reaction monitoring (MRM) mode was applied. The within-run and between-run precisions (CV%) were determined and the results were 1.9% and 3.9% for lactate (n=20) and 5.7% and 7.3% for Pyruvate (n=20). The linearity of lactate (r=0.9986) and Pyruvate (r=0.9973) based on the IS was excellent. The parameter r squared (r(2)) of linear regression between LC-MS/MS method and enzymatic assay was 0.9405 for lactate and 0.9447 for Pyruvate, respectively, and the agreement between these methods was consistent and acceptable. The stability of lactate and Pyruvate on DBS was also confirmed. The LC-MS/MS method we developed is a specific, sensitive, and reproducible method for measuring blood lactate and Pyruvate concentrations. The use of DBS in this method makes it particularly attractive for pediatric patients.

Med Intensiva. 2009 Nov; 33(8): 385-92
Regueira T, Andresen M, Djafarzadeh S

There is a direct correlation between the development of the multiple organ dysfunction syndrome (MODS) and the elevated mortality associated with sepsis. The mechanisms responsible for MODS development are being studied, however, the main efforts regarding MODS evaluation have focused on oxygen delivery optimization and on the modulation of the characteristic inflammatory cascade of sepsis, all with negative results. Recent studies have shown that there is development of tissue acidosis, even when there are normal oxygen conditions and limited presence of tissue cellular necrosis or apoptosis, which would indicate that cellular energetic dysfunction may be a central element in MODS pathogenesis. Mitochondrias are the main source of cellular energy, central regulators of cell death and the main source for reactive oxygen species. Several mechanisms contribute to mitochondrial dysfunction during sepsis, that is blockage of Pyruvate entry into the Krebs cycle, oxidative phosphorylation substrate use in other enzymatic complexes, enzymatic complex inhibition and membrane damage mediated by oxidative stress, and reduction in mitochondrial content. Hypoxia-inducible factor-1? (HIF-1?) is a nuclear transcription factor with a central role in the regulation of cellular oxygen homeostasis. Its induction under hypoxic conditions is associated to the expression of hundreds of genes that coordinate the optimization of cellular oxygen delivery and the cellular energy metabolism. HIF-1? can also be stabilized under normoxic condition during inflammation and this activation seems to be associated with a prominent pro-inflammatory profile, with lymphocytes dysfunction, and to a reduction in cellular oxygen consumption. Further studies should establish a role for HIF-1? as a therapeutic target.

Diabetologia. 2009 Nov 12;
Frigerio F, Brun T, Bartley C, Usardi A, Bosco D, Ravnskjær K, Mandrup S, Maechler P

AIMS/HYPOTHESIS: Pancreatic beta cells chronically exposed to fatty acids may lose specific functions and even undergo apoptosis. Generally, lipotoxicity is triggered by saturated fatty acids, whereas unsaturated fatty acids induce lipodysfunction, the latter being characterised by elevated basal insulin release and impaired glucose responses. The peroxisome proliferator-activated receptor alpha (PPARalpha) has been proposed to play a protective role in this process, although the cellular mechanisms involved are unclear. METHODS: We modulated PPARalpha production in INS-1E beta cells and investigated key metabolic pathways and genes responsible for metabolism-secretion coupling during a culture period of 3 days in the presence of 0.4 mmol/l oleate. RESULTS: In INS-1E cells, the secretory dysfunction primarily induced by oleate was aggravated by silencing of PPARalpha. Conversely, PPARalpha upregulation preserved glucose-stimulated insulin secretion, essentially by increasing the response at a stimulatory concentration of glucose (15 mmol/l), a protection we also observed in human islets. The protective effect was associated with restored glucose oxidation rate and upregulation of the anaplerotic enzyme Pyruvate carboxylase. PPARalpha overproduction increased both beta-oxidation and fatty acid storage in the form of neutral triacylglycerol, revealing overall induction of lipid metabolism. These observations were substantiated by expression levels of associated genes. CONCLUSIONS/INTERPRETATION: PPARalpha protected INS-1E beta cells from oleate-induced dysfunction, promoting both preservation of glucose metabolic pathways and fatty acid turnover.

Bull Exp Biol Med. 2009 Jul; 148(1): 137-9
Bogorodskaya SL, Clinova SN, Gutnik IN, Pivovarov JI, Kurilskaya TE, Runovich AA

The effects of transplantation of xenogenic neonatal heart cells on energy processes were studied in rat myocardium during the early period of epinephrine injury. Transplantation promoted a less pronounced ATP hydrolys to adenosine monophosphate and inorganic phosphate, a higher level of creatine phosphate, Pyruvate, lactate, retention and activation of myocardial enzymes involved in energy metabolism.

FEBS J. 2009 Nov 6;
Spitznagel D, Ebikeme C, Biran M, Nic A Bháird N, Bringaud F, Henehan GT, Nolan DP

African trypanosomes possess high levels of alanine aminotransferase (EC 2.6.1.2), although the function of their activity remains enigmatic, especially in slender bloodstream forms where the metabolism of ketoacids does not occur. Therefore, the gene for alanine aminotransferase enzyme in Trypanosoma brucei (TbAAT) was characterized and its function assessed using a combination of RNA interference and gene knockout approaches. Surprisingly, as much as 95% or more of the activity appears to be unnecessary for growth of either bloodstream or procyclic forms respiring on glucose. A combination of RNA interference and NMR spectroscopy revealed an important role for the activity in procyclic forms respiring on proline. Under these conditions, the major end product of proline metabolism is alanine, and a reduction in TbAAT activity led to a proportionate decrease in the amount of alanine excreted along with an increase in the doubling time of the cells. These results provide evidence of a role for alanine aminotransferase in the metabolism of proline in African trypanosomes by linking glutamate produced by the initial oxidative steps of the pathway with Pyruvate produced by the final oxidative step of the pathway. This step appears to be essential when proline is the primary carbon source, which is likely to be the physiological situation in the tsetse fly vector.

Int J Radiat Biol. 2009 Nov; 85(11): 963-71
Sattler UG, Mueller-Klieser W

PURPOSE: In this mini-review data are summarised which provide evidence for the biological and clinical significance of tumour glycolysis and of its relationship to the redox state of cancer cells. RESULTS: Malignant transformation is associated with an overexpression of numerous glycolysis-related genes in the vast majority of human cancers. At the same time, glycolytic activity and glycolysis-linked metabolic milieu are often variable between individual tumours which induces large variations in treatment response and aggressiveness. Currently, there is no genetic or proteomic marker for the prediction of the therapeutic response for individual tumours, but the prognostic value of tumour lactate accumulation for the emergence of metastasis, for patient survival and for radioresistance has been documented in a number of studies. CONCLUSIONS: Transactivation of tumour glycolyis appears to generate a chemically reduced milieu associated with an inhibition of ROS (reactive oxygen species) -mediated fixation of DNA damage and induction of radioresistance. Furthermore, highly glycolytic cells enhance the antioxidant defense via glutathione, and Pyruvate can be decarboxylated non-enzymatically upon reducing hydrogen peroxide. The summary of data given here emphasises the importance of further research efforts on the link between carbohydrate metabolism and redox state of cancer cells.

Fish Physiol Biochem. 2009 Nov 6;
Enes P, Peres H, Couto A, Oliva-Teles A

The effect of dietary carbohydrate complexity on growth, feed utilization and activity of selected key liver enzymes of intermediary metabolism were studied in gilthead sea bream juveniles. Four isonitrogenous (50% crude protein) and isolipidic (16% crude lipids) diets were formulated to contain 20% of pregelatinized maize starch, dextrin, maltose or glucose. Triplicate groups of fish (117 g initial weight) were fed each diet to near satiation during 6 weeks. No effect of dietary carbohydrate on growth was noticed. Feed efficiency was lower in fish fed the glucose diet than the maltose and dextrin diets. The lowest protein efficiency ratio was observed in fish fed the glucose diet. Six hours after feeding, glycemia was higher in fish fed the glucose diet than the maltose and starch diets. Liver glycogen content was unaffected by dietary carbohydrate complexity. Hepatic glucokinase (GK) activity was higher in fish fed the glucose and the maltose diets, while higher Pyruvate kinase (PK) activity was recorded in fish fed the glucose diet than in fish fed the starch diet. Fructose-1,6-bisphosphatase (FBPase) and glucose-6-phosphate dehydrogenase (G6PD) activities were higher in fish fed the starch diet compared to dextrin and glucose diets. Data suggest that dietary glucose and maltose are more effective than complex carbohydrates in enhancing liver glycolytic activity. Dietary glucose also seems to be more effective than starch in depressing liver gluconeogenic and lipogenic activities. Overall, dietary maltose, dextrin or starch was better utilized than glucose as energy source by gilthead sea bream juveniles.

Eur J Appl Physiol. 2009 Nov 6;
Sjøgaard G, Rosendal L, Kristiansen J, Blangsted AK, Skotte J, Larsson B, Gerdle B, Saltin B, Søgaard K

The aim of this investigation was to study female workers active in the labour market for differences between those with trapezius myalgia (MYA) and without (CON) during repetitive pegboard (PEG) and stress (STR) tasks regarding (1) relative muscle load, (2) trapezius muscle blood flow, (3) metabolite accumulation, (4) oxygenation, and (5) pain development. Among 812 female employees (age 30-60 years) at 7 companies with high prevalence of neck/shoulder complaints, clinical examination identified 43 MYA and 19 CON. At rest, during PEG, and STR the trapezius muscle was measured using (1) EMG and MMG, (2) microdialysis, and (3) NIRS. Further, subjective pain ratings were scored (VAS). EMGrms in %MVE (Maximal Voluntary EMG-activity), was significantly higher among MYA than CON during PEG (11.74 +/- 9.09 vs. 7.42 +/- 5.56%MVE) and STR (5.47 +/- 5.00 vs. 3.28 +/- 1.94%MVE). MANOVA showed a group and time effect regarding data from the microdialysis: for MYA versus CON group differences demonstrated lower muscle blood flow and higher lactate and Pyruvate concentrations. Potassium and glucose only showed time effects. NIRS showed similar initial decreases in oxygenation with PEG in both groups, but only in CON a significant increase back to baseline during PEG. VAS score at rest was highest among MYA and increased during PEG, but not for CON. The results showed significant differences between CON and MYA regarding muscle metabolism at rest and with PEG and STR. Higher relative muscle load during PEG and STR, insufficient muscle blood flow and oxygenation may account for the higher lactate, Pyruvate and pain responses among MYA versus CON.

Endocrinology. 2009 Nov 3;
Ribet C, Montastier E, Valle C, Bezaire V, Mazzucotelli A, Mairal A, Viguerie N, Langin D

This work aimed at characterizing the role of peroxisome proliferator-activated receptors (PPAR)alpha in human white adipocyte metabolism and at comparing PPARalpha and PPARgamma actions in these cells. Primary cultures of human fat cells were treated with the PPARalpha agonist GW7647 or the PPARgamma agonist rosiglitazone. Changes in gene expression were determined using DNA microrrays and quantitative RT-PCR. Western blot and metabolic studies were performed to identify the biological effects elicited by PPAR agonist treatments. GW7647 induced an up-regulation of beta-oxidation gene expression and increased palmitate oxidation. Unexpectedly, glycolysis was strongly reduced at transcriptional and functional levels by GW7647 leading to a decrease in Pyruvate and lactate production. Glucose oxidation was decreased. Triglyceride esterification and de novo lipogenesis were inhibited by the PPARalpha agonist. GW7647-induced alterations were abolished by a treatment with a PPARalpha antagonist. Small interfering RNA-mediated extinction of PPARalpha gene expression in hMADS adipocytes attenuated GW7647 induction of palmitate oxidation. Rosiglitazone had no major impact on glycolysis and beta-oxidation. Altogether these results show that PPARalpha can selectively up-regulate beta-oxidation and decrease glucose utilization in human white adipocytes.

J Neurosurg. 2009 Nov; 111(5): 908-9
Samuelsson C, Howells T, Kumlien E, Enblad P, Hillered L, Ronne-Engström E