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 goal of the present study was to discern the cellular mechanism(s) that contributes to the age-associated decrease in skeletal muscle aerobic capacity. Skeletal muscle mitochondrial content, a parameter of oxidative capacity, was significantly lower (25 and 20% calculated on the basis of citrate synthase and succinate dehydrogenase activities, respectively) in 24-mo-old Fischer 344 rats compared with 6-mo-old adult rats. Mitochondria isolated from skeletal muscle of both age groups had identical state 3 (ADP-stimulated) and ADP-stimulated maximal respiratory rates and phosphorylation potential (ADP-to-O ratios) with both nonlipid and lipid substrates. In contrast, mitochondria from 24-mo-old rats displayed significantly lower state 4 (ADP-limited) respiratory rates and, consequently, higher respiratory control ratios. Consistent with the tighter coupling, there was a 68% reduction in uncoupling protein-3 (UCP-3) abundance in mitochondria from elderly compared with adult rats. Congruent with the respiratory studies, there was no age-associated decrease in carnitine palmitoyltransferase I and carnitine palmitoyltransferase II activities in isolated skeletal muscle mitochondria. However, there was a small, significant decrease in tissue total carnitine content. It is concluded that the in vivo observed decrease in skeletal muscle aerobic capacity with advanced age is a consequence of the decreased mitochondrial density. On the basis of the dramatic reduction of UCP-3 content associated with decreased state 4 respiration of skeletal muscle mitochondria from elderly rats, we propose that an increased free radical production might contribute to the metabolic compromise in aging.
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PMID:Aging skeletal muscle mitochondria in the rat: decreased uncoupling protein-3 content. 1159 63

The relationships between in vivo (31)P magnetic resonance spectroscopy (MRS) and in vitro markers of oxidative capacity (mitochondrial function) were determined in 27 women with varying levels of physical fitness. Following 90-s isometric plantar flexion exercises, calf muscle mitochondrial function was determined from the phosphocreatine (PCr) recovery time constant, the adenosine diphosphate (ADP) recovery time constant, the rate of change of PCr during the initial 14 s of recovery, and the apparent maximum rate of oxidative adenosine triphosphate (ATP) synthesis (Q(max)). Muscle fiber type distribution (I, IIa, IIx), citrate synthase (CS) activity, and cytochrome c oxidase (COX) activity were determined from a biopsy sample of lateral gastrocnemius. MRS markers of mitochondrial function correlated moderately (P < 0.05) with the percentage of type IIa oxidative fibers (r = 0.41 to 0.66) and CS activity (r = 0.48 to 0.64), but only weakly with COX activity (r = 0.03 to 0.26, P > 0.05). These results support the use of MRS to determine mitochondrial function in vivo.
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PMID:Relation between in vivo and in vitro measurements of skeletal muscle oxidative metabolism. 1174 76

Matrix metalloproteinases (MMPs) have recently become interesting as potential anticancer drugs. RO-28-2653 is a promising compound because of its antimetastatic and antiangiogenic activities. Due to the structural similarity of RO-28-2653 to mitochondriotoxic agents, speculation has arisen that this substance might impair mitochondrial function. We, therefore, investigated the effects of RO-28-2653 on mitochondrial enzymes and on the functional properties of isolated mitochondria and skinned muscle fibers from rat hearts. Results were compared to the action of amytal and 2,4-dinitrophenol (2,4-DNP), both of which are well documented mitochondriotoxic compounds. In contrast to 2,4-DNP, RO-28-2653 did not uncouple oxidative phosphorylation, although higher concentrations of the compound did impair mitochondrial function. Using malate/pyruvate as substrate, 50 microM of RO-28-2653 inhibited mitochondrial respiration in isolated mitochondria and skinned fibers by 23 and 11%, respectively while 2mM of amytal elicited almost complete inhibition of the mitochondrial respiration. RO-28-2653 (50 micro) inhibited succinate-dependent respiration in both systems by 43 and 24%, respectively while 2mM of amytal caused 41 and 23% inhibition, respectively. There was no change in the ADP/O ratios. RO-28-2653 (50 microM) did not significantly alter the activity of the respiratory chain complexes or succinate dehydrogenase, although citrate synthase (CS) was inhibited by upto 71%. This inhibition was non-competitive at a K(i) of 25+/-5 microM. Inhibitory effects in the presence of hydrophobic substances, such as BSA and Triton X-100, were significantly lower in both test systems. In conclusion, high concentrations of RO-28-2653 impair mitochondrial function, although compared to amytal and 2,4-DNP, this is rather low. The resultant impairment is less pronounced in the more complex skinned muscle fiber system, and is dependent on hydrophobic interactions.
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PMID:Effect of the new matrix metalloproteinase inhibitor RO-28-2653 on mitochondrial function. 1199 41

The purpose of this study was to determine whether muscle metabolic capacity was inversely related to age after adjusting for physical activity in sedentary premenopausal women. Eighty-three women (ages 23-47 yr) had their free-living, activity-related energy expenditure evaluated with doubly labeled water procedures, and room calorimeter determined sleeping energy expenditure. Maximum O(2) uptake and strength were evaluated in all subjects, whereas 31P-magnetic resonance spectroscopy determined metabolic economy during maximal exercise, and muscle biopsy maximal enzyme activity was evaluated in subsets of the sample (48 and 18 subjects, respectively). Age was significantly related to whole body treadmill endurance time (r = -0.32), plantar flexion strength (r = -0.29), maximum O(2) uptake (r = -0.27), (31)P-magnetic resonance spectroscopy ADP recovery rate (r = -0.44), and anaerobic glycolytic capacity (r = -0.37), and muscle biopsy citrate synthase activity (r = -0.48), glyceraldehyde-3-phosphate dehydrogenase (r = -0.54), phosphofructokinase (r = -0.62), and phosphorylase (r = -0.58) activity even after adjusting for activity-related energy expenditure. These data suggest that, in sedentary premenopausal women, both oxidative and glycolytic muscle capacity decrease with age even when physical activity is taken into account.
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PMID:Age is independently related to muscle metabolic capacity in premenopausal women. 1207 Jan 88

Oxidative capacity of muscles correlates with capillary density and with microcirculation, which in turn depend on various regulatory factors, including NO generated by endothelial nitric oxide synthase (eNOS). To determine the role of eNOS in patterns of regulation of energy metabolism in various muscles, we studied mitochondrial respiration in situ in saponin-permeabilized fibres as well as the energy metabolism enzyme profile in the cardiac, soleus (oxidative) and gastrocnemius (glycolytic) muscles isolated from mice lacking eNOS (eNOS(-/-)). In soleus muscle, the absence of eNOS induced a marked decrease in both basal mitochondrial respiration without ADP (-32%; P <0.05) and maximal respiration in the presence of ADP (-29%; P <0.05). Furthermore, the eNOS(-/-) soleus muscle showed a decrease in total creatine kinase (-29%; P <0.05), citrate synthase (-31%; P <0.01), adenylate kinase (-27%; P <0.05), glyceraldehyde-3-phosphate dehydrogenase (-43%; P <0.01) and pyruvate kinase (-26%; P <0.05) activities. The percentage of myosin heavy chains I (slow isoform) was significantly increased from 24.3+/-1.5% in control to 30.1+/-1.1% in eNOS(-/-) soleus muscle ( P <0.05) at the expense of a slight non-significant decrease in the three other (fast) isoforms. Besides, eNOS(-/-) soleus showed a 28% loss of weight. Interestingly, we did not find differences in any parameters in cardiac and gastrocnemius muscles compared with respective controls. These results show that eNOS knockout has an important effect on muscle oxidative capacity as well on the activities of energy metabolism enzymes in oxidative (soleus) muscle. The absence of such effects in cardiac and glycolytic (gastrocnemius) muscle suggests a specific role for eNOS-produced NO in oxidative skeletal muscle.
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PMID:Endothelial nitric oxide synthase (NOS) deficiency affects energy metabolism pattern in murine oxidative skeletal muscle. 1212 18

The use of tamoxifen (TAM) has been questioned on the chemotherapy and chemoprevention of breast cancer due to several estrogen receptor-independent cytotoxic effects. As an alternative, its more active metabolite 4-hydroxytamoxifen (OHTAM) has been proposed with presumed lower side effects. In this work, the potential OHTAM toxicity on rat liver mitochondrial bioenergetics in relation to the multiple deleterious effects of TAM was evaluated. OHTAM, at concentrations lower than those putatively reached in tissues following the administration of TAM, does not induce significant perturbations on the respiratory control ratio (RCR), ADP/O, transmembrane potential (DeltaPsi), phosphorylative capacity and membrane integrity of mitochondria. However, at high concentrations, OHTAM depresses the DeltaPsi, RCR and ADP/O, affecting the phosphorylation efficiency, as also inferred from the DeltaPsi fluctuations and pH changes associated with ADP phosphorylation. Moreover, OHTAM, at concentrations that stimulate the rate of state 4 respiration in parallel to the decrease in the DeltaPsi and phosphorylation rate, causes mitochondrial swelling and stimulates both ATPase and citrate synthase activities. However, the OHTAM-observed effects, at high concentrations, are not significant relatively to the damaging effects promoted by TAM and suggest alterations to mitochondrial functions due to proton leak across the mitochondrial inner membrane.
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PMID:4-Hydroxytamoxifen induces slight uncoupling of mitochondrial oxidative phosphorylation system in relation to the deleterious effects of tamoxifen. 1227 May 94

We have cloned, purified to homogeneity, and characterized as a molecular chaperone the Escherichia coli YedU protein. The purified protein shows a single band at 31 kDa on SDS-polyacrylamide gels and forms dimers in solution. Like other chaperones, YedU interacts with unfolded and denatured proteins. It promotes the functional folding of citrate synthase and alpha-glucosidase after urea denaturation and prevents the aggregation of citrate synthase under heat shock conditions. YedU forms complexes with the permanently unfolded protein, reduced carboxymethyl alpha-lactalbumin. In contrast to DnaK/Hsp70, ATP does not stimulate YedU-dependent citrate synthase renaturation and does not affect the interaction between YedU and unfolded proteins, and YedU does not display any peptide-stimulated ATPase activity. We conclude that YedU is a novel chaperone which functions independently of an ATP/ADP cycle.
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PMID:Characterization of the Escherichia coli YedU protein as a molecular chaperone. 1256 79

Previous studies suggested that administration of cyclosporin A (CsA), an immunosuppressive agent, contributes to the increased fatigability of heart transplant recipients. The aim of this study was to investigate whether CsA itself, without vehicle, affects the function of mitochondria maintained in situ, in rats treated with CsA (25mg/kg/day) dissolved in ethanol and olive oil. Treatment with CsA induced a 16% decrease in slow myosin heavy chain (MHC) associated with a 225% increase in fast MHCIIa. The proportion of fibers expressing type IIa MHC increased as a result of CsA treatment. Soleus from the CsA-treated animals showed an increase in both basal (+85%) and maximal (+37%) mitochondrial respiration (P < 0.001), consistent with a 24% increase in citrate synthase activity, whereas the apparent Km for adenosine diphosphate was unchanged. By itself, CsA has no deleterious effects on muscle oxidative capacity but induces alterations in energy metabolism in accordance with the increased proportion of fast-twitch oxidative fibers.
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PMID:Cyclosporin A treatment increases rat soleus muscle oxidative capacities. 1292 92

The time course of changes in the properties of mitochondria from oxidative muscle of rainbow trout was examined during warm (15 degrees C) and cold (5 degrees C) acclimation. Mitochondrial oxidative capacities showed a biphasic response during thermal acclimation: at a given assay temperature, capacities first increased and then decreased during warm acclimation and showed the inverse pattern during cold acclimation. This was most apparent for maximal rates of state 3 oxygen consumption expressed per mg mitochondrial protein. Rates expressed per nmol ADP-ATP translocase (ANT) showed this pattern during cold acclimation. A biphasic pattern was also apparent for state 4 and oligomycin-inhibited (state 4(ol)) rates of oxygen uptake expressed per mg protein. Changes in states 4 and 4(ol) were smaller during cold than warm acclimation. Warm acclimation reduced the proportion of cytochrome c oxidase and citrate synthase needed during mitochondrial substrate oxidation. Phospholipid concentrations per mg mitochondrial protein changed little with thermal acclimation. Mitochondrial properties changed more quickly during warm than cold acclimation. While the biochemical modifications during thermal acclimation may eventually compensate for the thermal change, compensation did not occur at its onset. Rather, the initial changes of mitochondrial oxidative capacity in response to temperature change accentuated the functional impact of the thermal change, and prolonged exposure to the new temperature was required to attain a degree of thermal compensation.
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PMID:Time course of the response of mitochondria from oxidative muscle during thermal acclimation of rainbow trout, Oncorhynchus mykiss. 1293 76

Mitochondrial proteins such as uncoupling protein 3 (UCP3) and adenine nucleotide translocase (ANT) may mediate back-leakage of protons and serve as uncouplers of oxidative phosphorylation. We hypothesized that UCP3 and ANT increase after prolonged exercise and/or endurance training, resulting in increased uncoupled respiration (UCR). Subjects were investigated with muscle biopsies before and after acute exercise (75 min of cycling at 70% of .VO2peak) or 6 weeks endurance training. Mitochondria were isolated and respiration measured in the absence (UCR or state 4) and presence of ADP (coupled respiration or state 3). Protein expression of UCP3 and ANT was measured with Western blotting. After endurance training, .VO2peak, citrate synthase activity (CS), state 3 respiration and ANT increased by 24, 47, 40 and 95%, respectively (all P < 0.05), whereas UCP3 remained unchanged. When expressed per unit of CS (a marker of mitochondrial volume) UCP3 and UCR decreased by 54% and 18%(P < 0.05). CS increased by 43% after acute exercise and remained elevated after 3 h of recovery (P < 0.05), whereas the other muscle parameters remained unchanged. An intriguing finding was that acute exercise reversibly enhanced the capacity of mitochondria to accumulate Ca2+(P < 0.05) before opening of permeability transition pores. In conclusion, UCP3 protein and UCR decrease after endurance training when related to mitochondrial volume. These changes may prevent excessive basal thermogenesis. Acute exercise enhances mitochondrial resistance to Ca2+ overload but does not influence UCR or protein expression of UCP3 and ANT. The increased Ca2+ resistance may prevent mitochondrial degradation and the mechanism needs to be further explored.
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PMID:Effects of acute and chronic endurance exercise on mitochondrial uncoupling in human skeletal muscle. 1463 2


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