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)

A reduction in exercise capacity is a common feature of congestive heart failure. We hypothesized that depressed aerobic enzyme activity of skeletal muscle may contribute to this exercise intolerance. Biopsy samples of vastus lateralis muscle were obtained from seven patients with severe chronic heart failure and analyzed for aerobic enzyme activity. Compared with normal laboratory controls, the patients with heart failure had a moderate reduction (greater than 60%) in skeletal muscle citrate synthase and a marked reduction (greater than 90%) in succinate dehydrogenase and cytochrome oxidase (all p less than 0.001). Depression of aerobic enzyme activity of skeletal muscle is associated with severe chronic heart failure and is likely one of the contributory factors for impaired exercise capacity seen in the advanced stages of this condition.
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PMID:Depressed aerobic enzyme activity of skeletal muscle in severe chronic heart failure. 185 Apr 46

31P nuclear magnetic resonance (NMR) was used to examine the metabolism of skeletal muscle in rats 6-8 wk after myocardial infarction (MI). These in vivo measurements were supplemented by measurement of creatine, phosphocreatine (PCr), and ATP in freeze-clamped muscle using high-performance liquid chromatography (HPLC) and assays of key muscle enzymes to better define the muscle abnormality observed in heart failure. Resting PCr/(PCr + Pi) and pH were similar in MI rats and controls. Rats with MI had lower pH and PCr/(PCr + Pi) than controls during sciatic nerve stimulation at 1 and 2 Hz. These changes were more severe in rats with large (greater than or equal to 46%) infarcts, and changes in pH and PCr/(PCr + Pi) were correlated with infarct size. Free [ADP] in vivo was estimated from the NMR and HPLC measurements. [ADP] was increased in rats with large infarcts during nerve stimulation, implying a defect in oxidative metabolism. Citrate synthase, a mitochondrial enzyme, was reduced in rats with large MI. Citrate synthase levels were correlated with changes in PCr/(PCr + Pi) at 2 Hz. The NMR changes in skeletal muscle can be explained by reduced oxidative capacity of skeletal muscle, and this proposition is supported by the demonstration of reduced citrate synthase levels in skeletal muscle of rats with large infarcts.
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PMID:Skeletal muscle metabolism in heart failure in rats. 187 70

Recent studies in patients with long-term heart failure have suggested that intrinsic abnormalities in skeletal muscle can contribute to the development of early lactic acidosis and fatigue during exercise. The present study provides an analysis of substrate and enzyme content, fiber typing, and capillarization in skeletal muscle biopsy samples obtained at rest from the vastus lateralis in 11 patients with long-term heart failure (left ventricular ejection fraction, 21 +/- 8%) and nine normal subjects. Patients demonstrated a reduced peak exercise oxygen consumption (13.0 +/- 3.3 ml/kg/min) when compared with normals (30.2 +/- 8.6 ml/kg/min, p less than 0.001) and had an accelerated rise in blood lactate levels during exercise. In mixed fiber skeletal muscle, total phosphorylase and glycolytic enzyme activities were not different in the two groups, whereas mitochondrial enzymes involved in terminal oxidation were decreased in patients as compared with normal subjects as indicated by reductions in succinate dehydrogenase (51 +/- 15 vs. 81 +/- 17 microM/g protein/min, p less than 0.001) and citrate synthetase (26 +/- 7 vs. 43 +/- 20 microM/g protein/min, p less than 0.05). 3-Hydroxyacyl-CoA-dehydrogenase, an important enzyme mediating beta-oxidation of fatty acids, was also reduced in patients as compared with normals (18 +/- 7 vs. 27 +/- 10 microM/g protein/min, p less than 0.05). There was no difference in high-energy phosphagens or lactate concentration of mixed muscle in the two groups, whereas glycogen content was decreased in patients (262 +/- 29 vs. 298 +/- 35 microM glucosyl units/kg dry wt, p = 0.01). Patients demonstrated a reduced percentage of slow twitch type I fibers (36 +/- 7% vs. 52 +/- 22%, p less than 0.05) and had a higher percentage of type IIb fast twitch fibers (24 +/- 9% vs. 11 +/- 12%, p = 0.02), which were smaller than the type IIb fibers seen in normal subjects (p less than 0.05). In patients, the number of capillaries per fiber was decreased for type I and type IIa fibers (both, p less than 0.03), but the ratio of capillaries to cross-sectional fiber area was not different for the two groups. These data demonstrate major alterations in skeletal muscle histology and biochemistry in patients with long-term heart failure, including fiber atrophy, a decrease in percentage of composition of type I fibers, and an increase in type IIb fibers accompanied by a decrease in oxidative enzyme capacity.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Skeletal muscle biochemistry and histology in ambulatory patients with long-term heart failure. 229 59

Patients with heart failure frequently exhibit abnormal skeletal muscle metabolic responses to exercise, as assessed with 31P NMR. To investigate whether these metabolic abnormalities are due to intrinsic skeletal muscle changes, we performed gastrocnemius muscle biopsies on 22 patients with heart failure (peak VO2, 15.4 +/- 4.7 ml/kg/min; ejection fraction, 20 +/- 7%) and on eight normal subjects. Biopsies were analyzed for fiber type and area, capillarity, citrate synthase, phosphofructokinase, lactate dehydrogenase, and beta-hydroxyacyl CoA dehydrogenase activity. All patients with heart failure also underwent 31P NMR studies of their calf muscle during plantarflexion at three workloads. Muscle pH responses and the relation of the ratio of inorganic phosphate to phosphocreatine (Pi/PCr) to systemic VO2 were then evaluated. Compared with normal subjects, patients with heart failure exhibited a shift in fiber distribution with increased percentage of the fast twitch, glycolytic, easily fatigable type IIb fibers (normal subjects, 22.7 +/- 10.1; heart failure, 33.1 +/- 11.1%; p less than 0.05), atrophy of type IIa (normal subjects, 5,477 +/- 1,109; heart failure, 4,239 +/- 1,247 microns 2; p less than 0.05) and type IIb fibers (normal subjects, 5,957 +/- 1,388; heart failure, 4,144 +/- 945 microns 2; p less than 0.01), and decreased activity of beta-hydroxyacyl CoA dehydrogenase (normal subjects, 5.17 +/- 1.44; heart failure, 3.67 +/- 1.68 mol/kg protein/hr; p less than 0.05). No significant linear correlation could be identified between the slope of the Pi/PCr to VO2 relation and muscle histochemistry or enzyme activities. Similarly, no linear relation was found between intracellular pH at peak exercise and any muscle variable.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Contribution of intrinsic skeletal muscle changes to 31P NMR skeletal muscle metabolic abnormalities in patients with chronic heart failure. 280 70

Experimental hyperthyroidism induced in rats by daily injections of 3,3',5,5'-tetraiode-L-thyroxine (0.5 mg/kg i.p.) for 14 days resulted in a significant increase in heart weight and heart weight/body weight ratio. Hemodynamic and morphological studies were performed in one group. Thyroxine-treated rats showed a characteristic cardiovascular hyperdynamic state, such as tachycardia and augmented rate of contraction, but no evidence of heart failure such as elevated end-diastolic pressures. The cardiac cells in hyperthyroid rats had a significantly larger diameter and more mitochondria than did those of the control rats. In another group the activities of cardiac enzymes involved in energy utilization and liberation were measured biochemically and compared with those of normal controls. Hyperthyroidism resulted in increased specific activity of cytochrome C oxidase and actomyosin ATPase in the myocardium. The specific activity of long-chain acyl-CoA synthetase, carnitine palmityl-transferase, carnitine acetyltransferase, malate dehydrogenase and citrate synthase showed a moderate to marked increment, whereas the specific activity of lactate dehydrogenase and pyruvate kinase remained at the control values. These results suggest that in hyperthyroid rat hearts the functions of both energy liberation and utilization systems are enhanced to meet the added workload. Moreover, the increased activity of the enzymes participating in fatty acid metabolism suggest that in thyroxine-induced hypertrophic and hyperdynamic rat hearts, fatty acids contribute more to the energy supply than do carbohydrates.
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PMID:Biochemical and morphological study of cardiac hypertrophy. Effects of thyroxine on enzyme activities in the rat myocardium. 315 81

Concentric left ventricular hypertrophy was produced in puppies by coarctation banding of the aorta at age 7 weeks. Hemodynamic, morphologic and biochemical studies were carried out 18 months after the operation. Systolic blood pressure proximal to the aortic constriction was 216 +/- 16 mmHg in experimental dogs compared with 115 +/- 5 mmHg in littermate control dogs. Ejection fraction of control and experimental dogs were 59 +/- 4 and 64 +/- 7, respectively. The left ventricular end-diastolic pressure was 6.0 +/- 0.4 in control and 8.4 +/- 1.1 in experimental dogs. There was no sign of overt heart failure in the experimental dogs. Anatomical analysis of different regions of the heart indicated that LV mass in the experimental dogs was increased by about 60%. Ultrastructure of mitochondria in situ, as observed under electron microscope, was normal both in control and hypertrophic hearts. Mitochondria isolated from epicardial and endocardial regions of the stable hypertrophic hearts showed normal rates of respiration, phosphorylation, citrate synthase, and cytochrome c oxidase activities compared to those isolated from hearts of littermate control dogs. It was, therefore, concluded that mitochondrial function is adequately preserved to meet the increased demand for energy in this model of stable cardiac hypertrophy of long duration.
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PMID:Mitochondrial function in canine experimental cardiac hypertrophy. 630 71

Skeletal muscle metabolic abnormalities exist in chronic heart failure. The influence of physical training on muscle metabolism after myocardial infarction was studied in a rat model. 31P magnetic resonance spectroscopy and enzyme assays were performed in Wistar rats 12 weeks after coronary artery ligation. Infarcted rats were allocated randomly to either 6 weeks of training or non-training. Spectra were collected from the calf muscles during sciatic nerve stimulation at 2 Hz. Fibre typing and enzymatic assays were performed on the muscles of the contralateral non stimulated leg. Post-mortem rats were also divided into severe and moderate heart failure according to the lung weight per body weight. At 200 g twitch tension, phosphocreatine and pH were found to be significantly lower in the non-trained severe heart failure group compared with the other groups. Phosphocreatine recovery half-time was significantly longer in the non-trained group with severe heart failure and correlated with the citrate synthase activity in the muscle. The training did not induce a change in the enzyme activities in the infarcted animals with moderate heart failure but did correct the lower citrate synthase activity in the non-trained severe heart failure animals. This normalization of muscle metabolism was achieved by training without any change in calf muscle mass, making atrophy unlikely to be the sole cause of the metabolic changes in heart failure. Training in rats with severe heart failure can reverse the abnormalities of skeletal muscle metabolism, implicating decreased physical activity in the aetiology of these changes.
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PMID:Rat skeletal muscle metabolism in experimental heart failure: effects of physical training. 748 70

Idiopathic dilated cardiomyopathy is associated with derangement of myocardial sarcoplasmic Ca-homeostasis and energy production. The molecular mechanism for these changes is unknown. Accordingly, we used genetic and experimentally-induced models of canine dilated cardiomyopathy and tested the hypothesis that these metabolic changes resulted from altered gene expression, as indicated by mRNA content. We studied dilated cardiomyopathy occurring naturally (n = 9) in Doberman pinschers, and in dogs subjected to rapid ventricular pacing (n = 5), in comparison with normal dogs (n = 9). We determined content and integrity of mRNA's using Northern and slot blotting, and measured activities of their translated product for the Ca-release channel and Ca-ATPase of sarcoplasmic reticulum, lactate dehydrogenase of glycolysis, citrate synthase of the tricarboxylic acid cycle, and for myoglobin, ATP-synthetase and the adenine nucleotide transporter, which are integral in oxidative phosphorylation. We found that, whereas both mRNA content and enzyme activity for markers of Ca-cycling, glycolysis, and oxidative phosphorylation were downregulated (20-80%) in dilated cardiomyopathy, they were upregulated (10-15%) for tricarboxylic acid cycling and for ribosomal RNA. RNA from cardiomyopathic tissue was up to 50% more degraded than for normal hearts in association with a 150% increase in ribonuclease activity. Downregulation of the Ca-cycle was asymmetric, with the Ca-channel being 65% more affected than the Ca-ATPase. This work supports the general paradigm that transcriptional and translational responses to pathophysiology are major determinants of the metabolic response seen in cardiac failure.
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PMID:Myocardial mRNA content and stability, and enzyme activities of Ca-cycling and aerobic metabolism in canine dilated cardiomyopathies. 777 66

Mitochondrial respiratory chain enzyme activities were measured in biopsies of left ventricular myocardium from 25 adults in 3 groups: cardiac transplant recipients with atherosclerotic coronary artery disease (CAD), transplant recipients with idiopathic dilated cardiomyopathy (IDC), and patients with compensatory left ventricular hypertrophy due to aortic valve stenosis (AS). Specific activities of complexes I + III and II + III were 21 +/- 12 and 58 +/- 21 nmol/min/mg of noncollagen protein, respectively, in CAD, and 56 +/- 21 and 96 +/- 57 nmol/min/mg, respectively, in IDC (p < 0.004 and < 0.03, respectively). Specimens from patients with AS had enzyme activities that were intermediate between those from patients with CAD and IDC. Myocardium of patients with transvalvular pressure gradients between 50 and 79 mm Hg showed low activities of complexes I + III and II + III (17 +/- 5 and 62 +/- 17 nmol/min/mg of noncollagen protein, respectively), whereas those with higher pressure gradients between 80 and 100 mm Hg had enzyme activities of complexes I + III and II + III equal to those in IDC (37 +/- 11 and 73 +/- 18 nmol/min/mg, respectively). The same results were obtained when enzyme activities were normalized for the activity of the mitochondrial matrix enzyme citrate synthase. The data suggest that a compensatory metabolic adaptation of the mitochondrial respiratory chain enzymes occurs in both AS and IDC. A reduction in enzyme activities that is observed in heart failure due to CAD and that may explain the contractile dysfunction in these patients cannot be confirmed in IDC. In IDC, the enzyme activities are sustained until very late in the disease.
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PMID:Myocardial respiratory chain enzyme activities in idiopathic dilated cardiomyopathy, and comparison with those in atherosclerotic coronary artery disease and valvular aortic stenosis. 839 43

In patients with congestive heart failure, skeletal muscle is characterized by a smaller proportion of slow-twitch oxidative fibers and reduced oxidative enzyme activity. However, whether these changes result from disuse or occur as a direct consequence of heart failure is unresolved. To address this issue, 18 rats with heart failure 8 weeks after left coronary artery ligation and 13 sham-operated control rats underwent quantification of locomotor activity by a photocell activation technique, measurements of hemodynamics and infarct size, histochemical and morphological analyses of the soleus and plantaris muscles, and Northern analyses of muscle contractile protein and oxidative enzyme mRNA expression. Although the rats with heart failure had elevated left ventricular end-diastolic pressures (24.1 +/- 2.6 mm Hg) and a mean infarct size of 35.1 +/- 4.1%, activity levels were similar to those found in the sham-operated rats (3849 +/- 304 versus 3526 +/- 130 counts per hour). With heart failure, there was a significant reduction of type I fibers in the soleus muscle and type IIa fibers in the plantaris muscle, with corresponding increases in intermediate staining of type IIab fibers in both muscles. This was associated with a 17% decrease in citrate synthase activity in both the soleus and plantaris muscles (26.2 +/- 1.6 versus 30.7 +/- 3.4 and 29.1 +/- 2.4 versus 35.7 +/- 3.4 mumol/L per minute per gram, respectively [P < .05]). In the soleus muscle, mRNA for both beta-myosin heavy chains and cytochrome C oxidase III (normalized to 18S RNA) was reduced (0.27 +/- 0.02 versus 0.65 +/- 0.02 and 0.23 +/- 0.04 versus 0.64 +/- 0.02 U), whereas the messages for IIx and IIb myosin heavy chains were increased. A similar decrease in messages for cytochrome oxidase and the primary myosin isoform was observed in the plantaris muscle. Both soleus beta-myosin heavy chain and cytochrome C oxidase expression show significant inverse relationships to left ventricular end-diastolic pressure and infarct size. In contrast, there was no relationship between either beta-myosin heavy chain or cytochrome C oxidase expression and locomotor activity. These results indicate that in rats heart failure produces changes in skeletal muscle gene expression at the pretranslational level that cannot be explained by inactivity.
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PMID:Heart failure in rats causes changes in skeletal muscle morphology and gene expression that are not explained by reduced activity. 892 60


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