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)

Endurance exercise training induces mitochondrial biogenesis in skeletal muscle. The peroxisome proliferator activated receptor co-activator 1alpha (PGC-1alpha) has recently been identified as a nuclear factor critical for coordinating the activation of genes required for mitochondrial biogenesis in cell culture and rodent skeletal muscle. To determine whether PGC-1alpha transcription is regulated by acute exercise and exercise training in human skeletal muscle, seven male subjects performed 4 weeks of one-legged knee extensor exercise training. At the end of training, subjects completed 3 h of two-legged knee extensor exercise. Biopsies were obtained from the vastus lateralis muscle of both the untrained and trained legs before exercise and after 0, 2, 6 and 24 h of recovery. Time to exhaustion (2 min maximum resistance), as well as hexokinase II (HKII), citrate synthase and 3-hydroxyacyl-CoA dehydrogenase mRNA, were higher in the trained than the untrained leg prior to exercise. Exercise induced a marked transient increase (P < 0.05) in PGC-1alpha transcription (10- to > 40-fold) and mRNA content (7- to 10-fold), peaking within 2 h after exercise. Activation of PGC-1alpha was greater in the trained leg despite the lower relative workload. Interestingly, exercise did not affect nuclear respiratory factor 1 (NRF-1) mRNA, a gene induced by PGC-1alpha in cell culture. HKII, mitochondrial transcription factor A, peroxisome proliferator activated receptor alpha, and calcineurin Aalpha and Abeta mRNA were elevated (approximately 2- to 6-fold; P < 0.05) at 6 h of recovery in the untrained leg but did not change in the trained leg. The present data demonstrate that exercise induces a dramatic transient increase in PGC-1alpha transcription and mRNA content in human skeletal muscle. Consistent with its role as a transcriptional coactivator, these findings suggest that PGC-1alpha may coordinate the activation of metabolic genes in human muscle in response to exercise.
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PMID:Exercise induces transient transcriptional activation of the PGC-1alpha gene in human skeletal muscle. 1256 9

Insulin resistance increases and muscle oxidative capacity decreases during aging, but lifestyle changes-especially physical activity-may reverse these trends. Here we report the effect of a 16-week aerobic exercise program (n = 65) or control activity (n = 37) performed by men and women aged 21-87 years on insulin sensitivity and muscle mitochondria. Insulin sensitivity, measured by intravenous glucose tolerance test, decreased with age (r = -0.32) and was related to abdominal fat content (r = -0.65). Exercise increased peak oxygen uptake (VO(2peak); 10%), activity of muscle mitochondrial enzymes (citrate synthase and cytochrome c oxidase, 45-76%) and mRNA levels of mitochondrial genes (COX4, ND4, both 66%) and genes involved in mitochondrial biogenesis (PGC-1alpha, 55%; NRF-1, 15%; TFAM, 85%). Exercise also increased muscle GLUT4 mRNA and protein (30-52%) and reduced abdominal fat (5%) and plasma triglycerides (25%). None of these changes were affected by age. In contrast, insulin sensitivity improved in younger people but not in middle-aged or older groups. Thus, the muscle mitochondrial response to 4 months of aerobic exercise training was similar in all age-groups, although the older people did not have an improvement in insulin sensitivity.
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PMID:Impact of aerobic exercise training on age-related changes in insulin sensitivity and muscle oxidative capacity. 1288 2

Changes in thyroid status are associated with profound alterations in biochemical and physiological functioning of cardiac muscle impacting metabolic rate, contractility and structural hypertrophy. Using an in vivo model of chronic treatment with thyroid hormone (T4, 0.3 mg/kg/day), we evaluated how mitochondria are regulated in response to T4, and assessed the relationship of T4-induced mitochondrial biogenesis and bioenergetics to overall cardiac hypertrophy. The role of thyroid hormone in cardiac bioenergetic remodeling was addressed in rats treated with T4 for 5, 10 and 15 days. Over that time, myocardial oxygen consumption substantially increased as did cardiac hypertrophy. Myocardial levels of mitochondrial enzyme activities, mitochondrial DNA (mtDNA), specific proteins and transcript were assessed. Activity levels of respiratory complexes I-V and citrate synthase significantly increased with 15 but not with 5 or 10-day T4 treatment. Myocardial levels of mtDNA, mitochondrial proteins (e.g. cytochrome c, cytochrome b, ATPase subunits, MnSOD) and the global transcription factor PPARalpha were significantly elevated with 15-day T4. Transcript analysis revealed increased expression of transcription factors and cofactors involved in mitochondrial biogenesis including PPARalpha, mtTFA, ErbAalpha and PGC-1alpha. Our findings indicate parallel increases in myocardial mitochondrial bioenergetic capacity, oxygen consumption and markers of mitochondrial biogenesis with 15-day T4; these changes were not present with 10-day T4 even with significant cardiac hypertrophy. The marked, parallel increases in PPARalpha levels suggest its potential involvement in mediating myocardial-specific remodeling of mitochondria in response to T4.
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PMID:Bioenergetic remodeling of heart mitochondria by thyroid hormone. 1554 39

Thyroid hormone (TH) is an important regulator of mitochondrial content and activity. As mitochondrial content and properties differ depending on muscle-type, we compared mitochondrial regulation and biogenesis by T3 in slow-twitch oxidative (soleus) and fast-twitch mixed muscle (plantaris). Male Wistar rats were treated for 21 to 27 days with T3 (200 microg/kg/day). Oxidative capacity, regulation of mitochondrial respiration by substrates and phosphate acceptors, and transcription factors were studied. In soleus, T3 treatment increased maximal oxygen consumption (Vmax) and the activities of citrate synthase (CS) and cytochrome oxidase (COX) by 100%, 45%, and 71%, respectively (P < 0.001), whereas in plantaris only Vmax increased, by 39% (P < 0.01). ADP-independent respiration rate was increased in soleus muscle by 216% suggesting mitochondrial uncoupling. Mitochondrial substrate utilization in soleus was also influenced by T3, as were mitochondrial enzymes. Lactate dehydrogenase (LDH) activity was elevated in soleus and plantaris by 63% and 11%, respectively (P < 0.01), and soleus creatine kinase was increased by 48% (P < 0.001). T3 increased the mRNA content of the transcriptional co-activator of mitochondrial genes, PGC-1alpha, and the I and IV COX subunits in soleus. The muscle specific response to thyroid hormones could be explained by a lower content of TH receptors in plantaris than soleus. Moreover, TRalpha mRNA level decreased further after T3 treatment. These results demonstrate that TH has a major effect on mitochondrial content, regulation and coupling in slow oxidative muscle, but to a lesser extent in fast muscle, due to the high expression of TH receptors and PGC-1alpha transcription factor.
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PMID:Differential effects of thyroid hormones on energy metabolism of rat slow- and fast-twitch muscles. 1560 82

Recent research suggests that LKB1 is the major AMP-activated protein kinase kinase (AMPKK). Peroxisome-proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) is a master coordinator of mitochondrial biogenesis. Previously we reported that skeletal muscle LKB1 protein increases with endurance training. The purpose of this study was to determine whether training-induced increases in skeletal muscle LKB1 and PGC-1alpha protein exhibit a time course and intensity-dependent response similar to that of citrate synthase. Male Sprague-Dawley rats completed endurance- and interval-training protocols. For endurance training, rats trained for 4, 11, 25, or 53 days. Interval-training rats trained identically to endurance-trained rats, except that after 25 days interval training was combined with endurance training. Time course data were collected from endurance-trained red quadriceps (RQ) after each time point. Interval training data were collected from soleus, RQ, and white quadriceps (WQ) muscle after 53 days only. Mouse protein 25 (MO25) and PGC-1alpha protein increased significantly after 4 days. Increased citrate synthase activity, increased LKB1 protein, and decreased AMPKK activity were found after 11 days. Maximal increases occurred after 4 days for hexokinase II, 25 days for MO25, and 53 days for citrate synthase, LKB1, and PGC-1alpha. In WQ, but not RQ or soleus, interval training had an additive effect to endurance training and induced significant increases in all proteins measured. These results demonstrate that LKB1 and PGC-1alpha protein abundances increase with endurance and interval training similarly to citrate synthase. The increase in LKB1 and PGC-1alpha with endurance and interval training may function to maintain the training-induced increases in mitochondrial mass.
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PMID:Endurance training increases skeletal muscle LKB1 and PGC-1alpha protein abundance: effects of time and intensity. 1601 50

AMPK is a key regulator of fat and carbohydrate metabolism. It has been postulated that defects in AMPK signaling could be responsible for some of the metabolic abnormalities of type 2 diabetes. In this study, we examined whether insulin-resistant obese Zucker rats have abnormalities in the AMPK pathway. We compared AMPK and ACC phosphorylation and the protein content of the upstream AMPK kinase LKB1 and the AMPK-regulated transcriptional coactivator PPARgamma coactivator-1 (PGC-1) in gastrocnemius of sedentary obese Zucker rats and sedentary lean Zucker rats. We also examined whether 7 wk of exercise training on a treadmill reversed abnormalities in the AMPK pathway in obese Zucker rats. In the obese rats, AMPK phosphorylation was reduced by 45% compared with lean rats. Protein expression of the AMPK kinase LKB1 was also reduced in the muscle from obese rats by 43%. In obese rats, phosphorylation of ACC and protein expression of PGC-1alpha, two AMPK-regulated proteins, tended to be reduced by 50 (P = 0.07) and 35% (P = 0.1), respectively. There were no differences in AMPKalpha1, -alpha2, -beta1, -beta2, and -gamma3 protein content between lean and obese rats. Training caused a 1.5-fold increase in AMPKalpha1 protein content in the obese rats, although there was no effect of training on AMPK phosphorylation and the other AMPK isoforms. Furthermore, training also significantly increased LKB1 and PGC-1alpha protein content 2.8- and 2.5-fold, respectively, in the obese rats. LKB1 protein strongly correlated with hexokinase II activity (r = 0.75, P = 0.001), citrate synthase activity (r = 0.54, P = 0.02), and PGC-1alpha protein content (r = 0.81, P < 0.001). In summary, obese insulin-resistant rodents have abnormalities in the LKB1-AMPK-PGC-1 pathway in muscle, and these abnormalities can be restored by training.
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PMID:LKB1-AMPK signaling in muscle from obese insulin-resistant Zucker rats and effects of training. 1635 71

Aging induces complex changes in myocardium bioenergetic and contractile properties. Using F344BNF(1) rats, we examined age-dependent changes in myocardial bioenergetic enzymes (catalytic activities and transcript levels) and mRNA levels of putative transcriptional regulators of bioenergetic genes. Very old rats (35 months) showed a 22% increase in ventricular mass with no changes in DNA or RNA per gram. Age-dependent cardiac hypertrophy was accompanied by complex changes in mitochondrial enzymes. Enzymes of the Krebs cycle and electron transport system remained within 15% of the values measured in adult heart, significant decreases occurring in citrate synthase (10%) and aconitase (15%). Transcripts for these enzymes were largely unaffected by aging, although mRNA levels of putative transcriptional regulators of the enzymes (nuclear respiratory factor (NRF) 1 and 2 alpha subunit) increased by about 30%-50%. In contrast, enzymes of fatty acid oxidation exhibited a more diverse pattern, with a 50% decrease in beta-hydroxyacyl-CoA dehydrogenase (HOAD) and no change in long-chain acyl-CoA dehydrogenase or carnitine palmitoyltransferase. Transcript levels for fatty acid oxidizing enzymes covaried with HOAD, which declined significantly by 30%. There were no significant changes in the relative transcript levels of regulators of genes for fatty acid oxidizing enzymes: peroxisome proliferator-activated receptor-alpha (PPARalpha), PPARbeta, or PPARgamma coactivator-1alpha (PGC-1alpha). There were no changes in the mRNA levels of Sirt1, a histone-modifying enzyme that interacts with PGC-1alpha. Collectively, these data suggest that aging causes complex changes in the enzymes of myocardial energy metabolism, triggered in part by NRF-independent pathways as well as post-transcriptional regulation.
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PMID:Control of mitochondrial gene expression in the aging rat myocardium. 1660

Heart failure is associated with alterations in cardiac and skeletal muscle energy metabolism resulting in a generalized myopathy. We investigated the molecular and cellular effects of angiotensin-converting enzyme inhibition (ACEi) on skeletal muscle metabolism in infarcted animals. Myocardial infarction (MI) was obtained by left descending coronary artery ligation. Sham, MI, and MI-treated rats (perindopril, 2 mg.kg(-1).day(-1) given 7 days after MI) were studied 1 and 4 mo after surgery. Oxygen consumption of white gastrocnemius (Gas) muscle was studied in saponin-permeabilized fibers, using the main substrates of mitochondrial respiration. mRNA expression of nuclear factors (PGC-1alpha, NRF-2alpha, and mtTFA), involved in the transcription of mitochondrial proteins, and of MCIP1, a marker of calcineurin activation, were also determined. Echocardiographic left ventricular fractional shortening was reduced in both MI and perindopril group after 1 and 4 mo, whereas systemic blood pressure was reduced by 16% only in the MI group after 4 mo. The capacity of Gas to oxidize glutamate-malate, glycerol-triphosphate, or pyruvate (-30%, P < 0.01; -32%, P < 0.05; -33%, P < 0.01, respectively), was greatly decreased. Furthermore, PGC-1alpha (-54%), NRF-2alpha (-45%), and MCIP1 (-84%) gene expression were significantly downregulated. ACEi improved survival, left ventricular function, and blood pressure. Perindopril protected also totally the Gas mitochondrial function and preserved the mRNAs concentration of the mitochondrial transcriptional factors. Moreover, PGC-1alpha correlated with Gas oxidative capacity (r = 0.48), mitochondrial cytochrome-c oxidase (r = 0.65), citrate synthase (r = 0.45) activities, and MCIP1 expression (r = 0.44). Thus ACEi totally prevented MI-induced alterations of skeletal muscle mitochondrial function and protein expression, halting the development of this metabolic myopathy.
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PMID:ACE inhibition prevents myocardial infarction-induced skeletal muscle mitochondrial dysfunction. 1661 54

Peroxisome proliferator-activated receptor-gamma coactivator-1alpha and -1beta (PGC-1alpha and PGC-1beta) 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-1alpha and PGC-1beta 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-1alpha enhanced glycogen buildup twofold at 5 or 25 mM glucose, whereas PGC-1beta caused a decrease. Both PGC-1alpha and PGC-1beta overexpression caused a faster maturation of myotubes, as seen by mRNA downregulation of the immature embryonal and perinatal myosin heavy-chain (MHC) isoforms. PGC-1alpha or PGC-1beta 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-1beta overexpression caused an increase in mRNA of the intermediary fast oxidative-associated MHC isoform MHCIIA. PGC-1alpha or PGC-1beta overexpression upregulated GLUT4 mRNA and downregulated myocyte enhancer factor 2C transcription factor mRNA; only PGC-1alpha overexpression caused an increase in the mRNA expression of TRB3, a negative regulator of insulin signaling. These results show that both PGC-1alpha and PGC-1beta are involved in the regulation of skeletal muscle fiber transition and metabolism and that they have both overlapping and differing effects.
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PMID:PGC-1alpha and PGC-1beta have both similar and distinct effects on myofiber switching toward an oxidative phenotype. 1672 Jun 25

We investigated if calorie restriction (CR) preserved skeletal muscle oxidative capacity with aging after accounting for life span extension by CR, and determined if mitochondrial content, mitochondrial DNA integrity, and peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha) were involved. Ad libitum-fed (AL) and CR animals representing young adult, late middle age, and senescence were studied. Whereas citrate synthase and complex IV activities were lower in plantaris and gastrocnemius muscle of young adult CR animals, in contrast to the 15%-40% decline in senescent AL animals, there was no decline with aging in CR animals. There was no decline in citrate synthase protein in gastrocnemius with aging in either group, suggesting that CR preserves oxidative capacity with aging by protecting mitochondrial function rather than content. This protection was independent of mitochondrial DNA damage between groups. However, there was a slower decline in PGC-1alpha gene expression with aging in CR versus AL animals, suggesting a better maintenance of mitochondrial biogenesis with aging in CR animals.
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PMID:No decline in skeletal muscle oxidative capacity with aging in long-term calorically restricted rats: effects are independent of mitochondrial DNA integrity. 1687 Jun 28


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