Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.3.3.1 (citrate synthase)
4,488 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The knee extensor and the whole-body exercise capacities were measured in 11 chronic heart failure (CHF) patients and 11 healthy age- and sex-matched controls, and were related to ejection fraction and to biochemical and histochemical markers of the musculature. The CHF patients had a 39% lower maximal oxygen uptake measured on an ergometer cycle than the healthy controls (1.54 +/- 0.57 vs. 2.51 +/- 0.70 1 min-1, P < 0.001). The low exercise capacity was markedly related to the ejection fraction (r = 0.77, P < 0.001). The maximal strength of m. quadriceps femoris was 15% lower in the CHF patients than in the controls (P < 0.05). The cross-sectional area (CSA) of m. quadriceps femoris explained 55% (r = 0.74, P < 0.001) of the difference in strength between both groups. The endurance capacity of m. quadriceps femoris was 30% lower in CHF patients than in controls, partly as a result of the 25% lower capillary density (P < 0.05) and the 27% lower aerobic enzyme capacity (P < 0.05), as estimated by the citrate synthase activity, in the CHF patients. The citrate synthase activity correlated with the maximal oxygen uptake (r = 0.61, P < 0.05). Moreover, the ejection fraction, together with the CSA of m. quadriceps femoris, explained 75% (r = 0.86%, P < 0.01) of the difference in maximal oxygen uptake between CHF patients and controls. These results demonstrate that CHF patients have both a lower local and a lower whole-body work capacity than healthy controls. This is a function of a smaller leg muscle mass and a lower capillary density and mitochondrial enzyme capacity in the CHF patients; however, a lowered pump capacity of the heart is the factor which limits the exercise capacity the most.
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PMID:Exercise capacity in heart failure patients: relative importance of heart and skeletal muscle. 896 35

Despite reported benefits of exercise training in men with chronic congestive heart failure (CHF) and in both men and women with coronary artery disease, the effects of training in women with CHF have not been throughly investigated. Therefore, 16 women (62 +/- 10 years [mean +/- SD]) with stable, moderate, chronic CHF (left ventricular ejection fraction 28 +/- 8%) were studied in a randomized crossover trial with 8 weeks of knee extensor endurance training and 8 weeks of nontraining. The effects of the exercise-based rehabilitation were assessed in skeletal muscle metabolic capacity, exercise tolerance, and quality of life. The compliance rate in training was 98% and no adverse events occurred during the study period. Training increased the activity of citrate synthase (44%, p <0.0001) and lactate dehydrogenase (23%, p <0.002) in the trained muscles, and an improved oxidative capacity in relation to the glycolytic capacity (23%, p <0.002) was found. Peak oxygen uptake (14%, p <0.0005) and peak work rate (43%, p <0.0001) during incremental exercise increased, and blood lactate concentration during standardized submaximal exercise and during the recovery phase decreased (17%, p <0.05). The distance ambulated during 6 minutes (p <0.03), and the overall (p <0.01), physical (p <0.05), and psychosocial (p <0.03) health-related quality of life improved. Because the skeletal muscle endurance training improved peripheral oxidative capacity, exercise tolerance, and the health-related quality of life without any adverse events, this mode of training can be recommended for women with chronic heart failure.
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PMID:Skeletal muscle endurance training improves peripheral oxidative capacity, exercise tolerance, and health-related quality of life in women with chronic congestive heart failure secondary to either ischemic cardiomyopathy or idiopathic dilated cardiomyopathy. 935 72

We report a new type of fatal mitochondrial disorder caused by selective deficiency of mitochondrial ATP synthase (ATPase). A hypotrophic newborn from a consanguineous marriage presented severe lactic acidosis, cardiomegaly and hepatomegaly and died from heart failure after 2 days. The activity of oligomycin-sensitive ATPase was only 31-34% of the control, both in muscle and heart, but the activities of cytochrome c oxidase, citrate synthase and pyruvate dehydrogenase were normal. Electrophoretic and western blot analysis revealed selective reduction of ATPase complex but normal levels of the respiratory chain complexes I, III and IV. The same selective deficiency of ATPase was found in cultured skin fibroblasts which showed similar decreases in ATPase content, ATPase hydrolytic activity and level of substrate-dependent ATP synthesis (20-25, 18 and 29-33% of the control, respectively). Pulse-chase labelling of patient fibroblasts revealed low incorporation of [(35)S]methionine into assembled ATPase complexes, but increased incorporation into immunoprecipitated ATPase subunit beta, which had a very short half-life. In contrast, no difference was found in the size and subunit composition of the assembled and newly produced ATPase complex. Transmitochondrial cybrids prepared from enucleated fibroblasts of the patient and rho degrees cells derived from 143B. TK(-)human osteosarcoma cells fully restored the ATPase activity, ATP synthesis and ATPase content, when compared with control cybrids. Likewise, the pattern of [(35)S]methionine labelling of ATPase was found to be normal in patient cybrids. We conclude that the generalized deficiency of mitochondrial ATPase described is of nuclear origin and is caused by altered biosynthesis of the enzyme.
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PMID:A novel deficiency of mitochondrial ATPase of nuclear origin. 1048 64

Men with chronic heart failure (CHF) have alterations in their skeletal muscle that are partially responsible for a decreased exercise tolerance. The purpose of this study was to investigate whether skeletal muscle alterations in women with CHF are similar to those observed in men and if these alterations are related to exercise intolerance. Twenty-five men and thirteen women with CHF performed a maximal exercise test for evaluation of peak oxygen consumption (VO(2)) and resting left ventricular ejection fraction, after which a biopsy of the vastus lateralis was performed. Twenty-one normal subjects (11 women, 10 men) were also studied. The relationship between muscle markers and peak VO(2) was consistent for CHF men and women. When controlling for gender, analysis showed that oxidative enzymes and capillary density are the best predictors of peak VO(2.) These results indicate that aerobically matched CHF men and women have no differences in skeletal muscle biochemistry and histology. However, when CHF groups were separated by peak exercise capacity of 4.5 metabolic equivalents (METs), CHF men with peak VO(2) >4.5 METs had increased citrate synthase and 3-hydroxyacyl-CoA dehydrogenase compared with CHF men with peak VO(2) <4.5 METs. CHF men with a lower peak VO(2) had increased capillary density compared with men with higher peak VO(2). These observations were not reproduced in CHF women. This suggests that differences may exist in how skeletal muscle adapts to decreasing peak VO(2) in patients with CHF.
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PMID:Differences in skeletal muscle between men and women with chronic heart failure. 1113 20

Intrinsic changes in skeletal muscle are being increasingly suspected as part of the underlying cause of exercise intolerance in patients with chronic heart failure (CHF). The objective of the present study was to determine whether differences existed between CHF patients and age-matched healthy controls in the concentration of skeletal muscle Na(+)-K(+)-ATPase (adenosine triphosphatase), a cation pump that functions to restore Na(+)-K(+) gradients and protect membrane excitability. Moreover, given the potency for physical activity in altering long-term regulation of the pump, an additional objective was to examine the role of activity level in pump expression in CHF patients. Na(+)-K(+)-ATPase concentration (pmol/g wet wt) determined in the vastus lateralis muscle of 27 CHF males (ejection fraction, 23 +/- 1.6%), using the vanadate facilitated [(3)H] ouabain binding technique, was not different (264 +/- 10) from 10 sedentary controls (268 +/- 19,P > 0.05). Similarly, no differences (P > 0.05) could be found between female patients (228 +/- 16, n = 7) and controls (243 +/- 13, n = 9). Differences between untrained control (294 +/- 20, n = 7), chronically active (251 +/- 20, n = 9), and trained (252 +/- 16, n = 6) CHF groups in Na(+)-K(+) pump expression were also insignificant. This study indicates that long-term regulation of Na(+)-K(+)-ATPase concentration is not altered in moderate CHF patients, regardless of the history of regular activity. However, the positive correlations (P < 0.05) that were observed between peak aerobic power (VO(2) peak) and Na(+)-K(+)-ATPase (r = 0.422) and VO(2) peak and maximal citrate synthase activity (r = 0.404) suggests a role for the skeletal muscle in explaining exercise intolerance in CHF patients.
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PMID:Normal skeletal muscle Na(+)-K(+) pump concentration in patients with chronic heart failure. 1115 Sep 68

The beta-adrenergic receptor system not only plays a central role in modulating heart rate and left-ventricular (LV) contractility, but is also involved in the development of heart failure. We have, recently, shown that heart-specific overexpression of the beta(1)-adrenergic receptor in transgenic mice (TG) initially leads to increased contractility, followed by LV hypertrophy and heart failure. Since one feature for all forms of heart failure are characteristic changes in myocardial energy metabolism, we asked whether alterations in energetics are detectable in these mice before signs of LV impairment are present. Myocardial energetics ((31)P NMR spectroscopy) and LV performance were measured simultaneously in isolated perfused hearts at different workloads. LV performance as well as contractile reserve was identical for hearts of 4-month-old TG and wild-type mice. The ratio of phosphocreatine to ATP (1.16 +/- 0.05 vs. 1.46 +/- 0.10) and total creatine content (17.6 +/- 1.2 vs. 22.6 +/- 0.9 mmol/l) were significantly reduced in TG. Furthermore, there was a significant decrease in creatine transporter content (-43%), mitochondrial (-44%) and total creatine kinase (CK) activity (-21%) as well as citrate synthase activity (-25%), indicating impaired oxidative energy generation in TG. In conclusion, these findings of alterations in the CK system, creatine metabolism and mitochondrial proteins in TG hearts prior to the development of LV dysfunction provide further evidence that changes in myocardial energetics play a central role in the deterioration of cardiac function after chronic beta-adrenergic stimulation.
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PMID:Alterations in the myocardial creatine kinase system precede the development of contractile dysfunction in beta(1)-adrenergic receptor transgenic mice. 1268 18

Recently, we have demonstrated that heart failure in rats is associated with a myopathy altering energy metabolism in different muscles, but the origin of this myopathy is still unknown. Here, we studied the possible involvement of increased angiotensin II (Ang II) by treatment with perindopril, an inhibitor of angiotensin-converting enzyme (ACE). The beneficial effects of ACE inhibition could result either from vasodilatation-induced cardiac unloading or from inhibition of the direct angiotensin action on the muscle cells. The model of aortic banding with persisting left ventricular (LV) overload where the cardiac unloading does not occur allows to distinguish between the two effects of ACE inhibition. Four months after aortic clipping (just before the treatment), echocardiographic study showed an impairment of the systolic function (decrease of the LV shortening by 30% and ejection fraction by 21%). Ten-week treatment with perindopril dramatically decreased Ang II plasma level but did not reduce LV hypertrophy though a significant decrease in right ventricular (RV) hypertrophy occurred. Perindopril did not improve alterations in activities of energy metabolism enzymes (creatine kinase, citrate synthase, cytochrome c oxidase, lactate dehydrogenase) either in ventricular or in skeletal (gastrocnemius) muscle. Similarly, ACE inhibition did not improve the main parameters of mitochondrial respiration in permeabilized muscle fibers. These data suggest that the generalized metabolic myopathy induced by the hemodynamic abnormalities conditioned by the continuous LV overload (aorta clipping) does not result from the increase in Ang II level per se. Correction of hemodynamic parameters and LV unloading seem to be the prerequisite for the improvement of muscle energy metabolism abnormalities.
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PMID:Does angiotensin-converting enzyme inhibition improve the energetic status of cardiac and skeletal muscles in heart failure induced by aortic stenosis in rats? 1268 19

Exercise capacity in patients with several types of cardiovascular disease can be improved with dietary carnitine, or carnitine derivatives. Mechanisms underlying this improvement remain largely unknown in part due to a lack of animal models of cardiac pathology in which carnitine derivatives improve exercise tolerance. Our goal was to evaluate the ability of propionyl-L-carnitine (PLC) to improve exercise tolerance in a rat model of exercise intolerance. Fischer 344 rats were followed after either a moderate size MI (n = 22) or sham MI surgery (n = 14). Starting 10 days post-surgery 10 of the MI and 7 of the sham rats received 100 mg/kg/day PLC in drinking water, which increased plasma and LV total l-carnitine concentrations 15-23% (p < 0.05). Rats were followed longitudinally until a statistically significant decrease in exercise capacity occurred in one of the groups, at which time all rats were sacrificed for study of the isolated perfused hearts. At 12-weeks post-MI exercise capacity had decreased 16 +/- 7% (p < 0.05) in the MI group, but remained within 3% of baseline in the MI group that received PLC and the sham groups. Both MI groups exhibited the same degree of LV dilation, decrease in fractional shortening, and blunting of the response to isoproterenol. We conclude that supplemental dietary PLC attenuates the exercise intolerance that occurs secondary to post-MI heart failure in rats, but that this beneficial effect is not attributable to altered LV remodeling, an improved response to beta-adrenergic stimulation, or increased skeletal muscle citrate synthase activity.
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PMID:Exercise intolerance during post-MI heart failure in rats: prevention with supplemental dietary propionyl-L-carnitine. 1284 82

Free fatty acid (FFA) oxidation is depressed in severe heart failure due to reduced activity of mitochondrial fatty acid oxidation enzymes. It is unknown whether the concomitant enhancement in cardiac glucose use is a consequence of reduced FFA oxidation, or also due to potentiation of the carbohydrate oxidative pathway. FFA and glucose oxidation rates were measured in vivo in 9 normal dogs and 9 dogs with pacing-induced heart failure by infusing (3)H-oleate and (14)C-glucose. FFA oxidation was lower (39 +/- 9 vs. 73 +/- 5 nmol min(-1) g(-1)), while glucose oxidation was higher (42 +/- 8 vs. 17 +/- 6 nmol min(-1) g(-1)) in failing compared to normal hearts (P < 0.05). At the end of the in vivo experiment, clamp-frozen biopsies were harvested from the left ventricle. Messenger RNAs encoding for proteins involved in both glucose and fatty acid metabolism, and for citrate synthase, were significantly reduced. Protein expression of GLUT-1 and GLUT-4, and GLUT-4 translocation to the sarcolemma showed no significant differences between the two groups despite a significant reduction in mRNAs with heart failure. GAPDH mRNA, protein expression, and activity were all reduced. The E2 subunit of pyruvate dehydrogenase was decreased both at the mRNA and protein level, with no effect on either fractional or maximal activity. In conclusion, we found either no changes or moderate downregulation of key enzymes of the carbohydrate metabolism in failing hearts, which suggests that the increase in glucose oxidation in vivo was principally due to impaired FFA oxidation and that the maximal myocardial capacity to obtain energy from substrate is globally depressed.
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PMID:Paradoxical downregulation of the glucose oxidation pathway despite enhanced flux in severe heart failure. 1508 16

Oxidative stress is involved in mitochondrial apoptosis, and plays a critical role in ischemic heart disease and cardiac failure. Exposure of cardiomyocytes to H(2)O(2) leads to oxidative stress and mitochondrial dysfunction. In this study, we investigated the temporal order of mitochondrial-related events in the neonatal rat cardiomyocyte response to H(2)O(2) treatment. At times ranging from 10 to 90 min after H(2)O(2) treatment, levels were determined for respiratory complexes I, II, IV and V, and citrate synthase activities, mitochondrial Ca(2+) flux, intracellular oxidation, mitochondrial membrane potential and apoptotic progression. Complexes II and IV activity levels were significantly reduced within 20 min of H(2)O(2) exposure while complexes I and V, and citrate synthase were unaffected. Mitochondrial membrane potential declined after 20 and 60 min of H(2)O(2) exposure while intracellular oxidation, declining complex I activity and apoptotic progression were detectable only after 60 min. Measurement of mitochondrial Ca(2+) ([Ca(2+)](m)) using rhodamine 2 detected an early accumulation of [Ca(2+)](m) occurring between 5 and 10 min. Pretreatment of cardiomyocytes with either ruthenium red or cyclosporin A abrogated the H(2)O(2)-induced decline in complexes II and IV activities, indicating that [Ca(2+)](m) flux and onset of mitochondrial permeability transition pore opening likely precede the observed early enzymatic decline. Our findings suggest that [Ca(2+)](m) flux represents an early pivotal event in H(2)O(2)-induced cardiomyocyte damage, preceding and presumably leading to reduced mitochondrial respiratory activity levels followed by accumulation of intracellular oxidation, mitochondrial membrane depolarization and apoptotic progression concomitant with declining complex I activity.
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PMID:Mitochondrial Ca2+ flux and respiratory enzyme activity decline are early events in cardiomyocyte response to H2O2. 1524 36


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