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Query: UMLS:C0015672 (fatigue)
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Recent investigations from our and other laboratories indicate that glycogen is a carbon-chain precursor in muscle for the synthesis of TCA cycle intermediates and glutamine. During intense exercise and in conditions of a relative lack of energy (hypoxia, trauma, sepsis) the metabolism of branched-chain amino acids (BCAA) is accelerated in muscle. In the primary BCAA aminotransferase reaction 2-oxoglutarate is used as amino-group acceptor (putting a carbon-drain on the TCA cycle) under formation of glutamate. Glutamate will subsequently react with ammonia, generated in the AMP deaminase reaction or by deamination of amino acids, under formation of glutamine in a reaction catalysed by glutamine synthetase (glutamate + ammonia + ATP--> glutamine + ADP). Muscle glycogen stores may be smaller or less available at high altitude. It is hypothesized that this will lead to premature fatigue (due to both a lack of fuel and of TCA cycle carbon-precursor) and to a reduction in the synthesis rate of glutamine. A chronic reduction in the synthesis rate of glutamine during a long term stay at high altitude on its turn may lead to gut atrophy, bacterial translocation, endotoxemia, muscle protein catabolism and a weakened immune status.
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PMID:Amino acid metabolism, muscular fatigue and muscle wasting. Speculations on adaptations at high altitude. 148 45

Severe lactic acidosis usually accompanies intense endurance exercise. It has been postulated that glycogen depletion working in concert with elevated muscle and plasma lactate levels lead to a concomitant reduction in pH. Their cumulative effect during prolonged physical exertion now leads to muscular fatigue and eventually limit endurance capacity. Therefore in the present study, dichloroacetate (DCA), a compound which enhances the rate of pyruvate oxidation thus reducing lactate formation, has been evaluated in a validated rat model of sub-maximal exercise performance. Male rats (350 g) were divided into two groups (control-saline, i.v. and DCA 5 mg/kg, i.v.) and were exercised to exhaustion in a chamber (26 degrees C) on a treadmill (11 m/min, 6 degrees incline). When compared to controls, the DCA-treated rats had longer run times (169 vs 101 min) and a decreased heating rate (0.020 vs 0.029 degrees C/min). In addition, DCA attenuated the increase in plasma lactate (28 vs 40 mg/dl) and significantly reduced both the rate and absolute amount of depletion of muscle glycogen stores. These results suggest that the activation of pyruvate dehydrogenase activity by DCA resulted in a reduction in the rate of glycogenolysis in addition to decreasing lactate accumulation by presumably limiting the availability of pyruvate for conversion to lactate, therefore increasing muscle carbohydrate oxidation via the TCA cycle. Thus DCA effected a significant delay in muscle fatigue.
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PMID:The effects of dichloroacetate on lactate accumulation and endurance in an exercising rat model. 764 7

Six amino acids are metabolized in resting muscle. They are leucine, isoleucine, valine, asparagine, aspartate, and glutamate. These amino acids provide the amino groups and probably the ammonia required for synthesis of glutamine and alanine, which are released in excessive amounts in the postabsorptive state and during ingestion of a protein-containing meal. Only leucine and part of the isolecine molecule can be oxidized in muscle as they are converted to acetyl-CoA. The other carbon skeletons are used solely for de novo synthesis of TCA-cycle intermediates and glutamine. The carbon atoms of the released alanine originate primarily from glycolysis of blood glucose and from muscle glycogen (about half each in resting conditions). After consumption of a protein-containing meal, BCAA and glutamate are taken up by muscle and their carbon skeletons are used for de novo synthesis of glutamine. About half of the glutamine released from muscle originates from glutamate taken up from the blood, both after overnight starvation, after prolonged starvation, and after consumption of a mixed meal. Glutamine produced by muscle is an important fuel and regulator of DNA and RNA synthesis in mucosal cells and immune system cells, and fulfils several other important functions in human metabolism. The alanine aminotransferase reaction functions to establish and maintain high concentrations of TCA-cycle intermediates in muscle during the first 10 min of exercise. The increase in concentration of TCA-cycle intermediates probably is needed to increase the flux of the TCA-cycle and meet the increased energy demand of exercise. A gradual increase in leucine oxidation subsequently leads to a carbon drain on the TCA-cycle in glycogen-depleted muscles, and may thus reduce the maximal flux in the TCA-cycle and lead to fatigue. Deamination of amino acids and glutamine synthesis present alternative anaplerotic mechanisms in glycogen-depleted muscles, but only allow exercise at 40-50% of Wmax. One-leg exercise leads to the net breakdown of muscle protein. The liberated amino acids are used for synthesis of TCA-cycle intermediates and glutamine. Today, the importance of this process in endurance exercise in the field (running or cycling) in athletes who ingest carbohydrates is not clear. It is proposed that the maximal flux in the TCA-cycle is reduced in glycogen-depleted muscles due to insufficient TCA-cycle anaplerosis, and that this presents a limitation for the maximal rate of fatty acid oxidation. Interactions between the amino acid pool and the TCA-cycle are suggested to play a central role in the energy metabolism of the exercising muscle.
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PMID:Muscle amino acid metabolism at rest and during exercise: role in human physiology and metabolism. 969 93

Muscle proteins turn over slowly and there are minimal diurnal changes in the size of the muscle protein pool in response to feeding and fasting. Nitrogen balance and tracer studies indicate that protein oxidation and net protein breakdown (degradation--synthesis) is not increased during dynamic exercise at intensities of < or = 70% VO2max. An imbalance between muscle protein synthesis and degradation does exist during one leg knee extensor exercise and during two legged cycling in patients with glycogen phosphorylase deficiency. In these latter cases amino acids liberated from the protein pool are used for synthesis of TCA-cycle intermediates and glutamine. Six amino acids are metabolized in resting muscle: leucine, isoleucine, valine, asparagine, aspartate and glutamate. Only leucine and part of the isoleucine molecule can be converted to acetylCoA and oxidized. The carbon skeleton of the other amino acids is used for synthesis of TCA-cycle intermediates and glutamine. The six amino acids provide the amino groups and the ammonia for synthesis of glutamine and alanine, which are released by muscle in excessive amounts. About half of the glutamine release from muscle originates from glutamate taken up from the blood. Glutamine produced by muscle is an important fuel and regulator of DNA and RNA synthesis in mucosal cells and immune system cells and fulfils several other important functions in human metabolism. The alanine aminotransferase reaction functions to establish and maintain high concentrations of TCA-cycle intermediates and a high TCA cycle flux in the first minutes of exercise. A gradual increase in leucine oxidation subsequently leads to a carbon drain on the TCA-cycle in glycogen depleted muscles and may thus reduce the maximal flux in the TCA-cycle and lead to fatigue. Deamination of amino acids and glutamine synthesis present alternative anaplerotic mechanisms in glycogen depleted muscles but only allow exercise at 40-50% of Wmax. It is proposed that the maximal flux in the TCA-cycle is reduced in glycogen depleted muscles due to insufficient TCA-cycle anaplerosis and that this presents a limitation for the maximal rate of fatty acid oxidation. Interactions between the amino acid pool and the TCA-cycle thus seem to play a central role in the energy metabolism of the exercising muscle.
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PMID:Protein and amino acid metabolism in human muscle. 978 36

Obesity has reached epidemic proportions and has become one of the major health problems in developed countries. Current theories consider obesity a result of overeating and sedentary life style and most efforts to treat or prevent weight gain concentrate on exercise and food intake. This approach does not improve the situation as may be seen from the steep increase in the prevalence of obesity. This encouraged us to reanalyse existing information and look for biochemical basis of obesity. Our approach was to ignore current theories and concentrate on experimental data which are described in scientific journals and are available from several databases. We developed and applied a Knowledge Discovery in Databases procedure to analyse metabolic data. We began with the contradictory information: in obesity, more calories are consumed than used up, suggesting that obese people should have excess energy. On the other side, obese people experience fatigue and decreased physical endurance that indicates diminished energy supply in the body. The result of our work is a chain of metabolic events leading to obesity. The crucial event is the inhibition of the TCA cycle at the step of aconitase. It disturbs energy metabolism and results in ATP deficiency with simultaneous fat accumulation. Further steps in obesity development are the consequences of diminished energy supply: inhibition of beta-oxidation, leptin resistance, increase in appetite and food intake and a decrease in physical activity. Thus, our theory shows that obesity does not have to be caused by overeating and sedentary life-style but may be the result of the "obese" change in metabolism which is forcing people to overeat and save energy to sustain metabolic functions of cells. This "obese" change is caused by environmental factors that activate chronic low-grade inflammatory process in the body linking obesity with the environment of developed countries.
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PMID:Decreased energy levels can cause and sustain obesity. 1455 57

The purpose of this study was to determine whether ingestion of a multinutrient supplement containing 3 tricarboxylic-acid-cycle intermediates (TCAIs; pyridoxine-alpha-ketoglutarate, malate, and succinate) and other substances potentially supporting the TCA cycle (such as aspartate and glutamate) would improve cyclists' time to exhaustion during a submaximal endurance-exercise test (approximately 70 % to 75 % VO2peak) and rate of recovery. Seven well-trained male cyclists (VO2max 67.4 2.1 mL x kg(-1) x in(-1), 28.6 +/- 2.4 y) participated in a randomized, double-blind crossover study for 7 wk. Each took either the treatment or a placebo 30 min before and after their normal training sessions for 3 wk and before submaximal exercise tests. There were no significant differences between the TCAI group (KI) and placebo group (P) in time to exhaustion during cycling (KI = 105 +/- 18, P = 113 +/- 11 min); respiratory-exchange ratio at 20-min intervals; blood lactate and plasma glucose before, after, and at 30-min intervals during exercise; perceived exertion at 20-min intervals during exercise; or time to fatigue after the 30-min recovery (KI = 16.1 +/- 3.2, P = 15 +/- 2 min). Taking a dietary sport supplement containing several TCAIs and supporting substances for 3 wk does not improve cycling performance at 75 % VO2peak or speed recovery from previously fatiguing exercise.
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PMID:Tricarboxylic-acid-cycle intermediates and cycle endurance capacity. 1565 76

Chronic pain, whether arising from viscera, bone, or any other tissue or structure, is, more often than commonly thought, the result of a mixture of pain mechanisms, and therefore there is no simple formula available to manage chronic complex pain states. Box 1 summarizes a pharmacological algorithm for difficult-to-treat chronic pain, which merely introduces the medication aspect of the treatment. In effect, any comprehensive algorithm should call for an interdisciplinary approach that would include rehabilitation, as well as psychosocial, and when indicated, interventional techniques. Box 1 Analgesic algorithm for difficult-to-treat pain syndromes. Pharmacological Interventions. Moderate to severe pain/functional impairment; pain with a score of >4 on the brief pain inventory. 1. Gabapentinoid (gabapentin, pregabalin)+/-Opioid/opioid rotation or 2. Antidepressant (TCA, duloxetine, venlafaxine)+/-Opioid/opioid rotation or 3. Gabapentinoid+antidepressant+Opioid/opioid rotation; in addition, may consider trials of one or more of the following adjuvants when clinically appropriate: Topical therapies for cutaneous allodynia/hyperalgesia. Anti-inflammatory drugs (corticosteroids for acute inflammatory neuropathic pain)IV bisphosphonates for cancer bone pain or CRPS/RSDNon-gabapentinoid AEDs such as carbamazepine or oxcarbazepine or lamotrigine+/-baclofen for intermittent lancinating pain due to cranial neuralgiasNMDA antagonists Mexiletine On a compassionate basis, according to the patient's clinical condition and pain mechanism, the physician may want to consider an empirical trial of one or more of the emergent topical, oral or parenteral/intrathecal therapies as discussed in the text. If SMP, consider topical clonidine and sympatholytic interventions; if clinically feasible, trials of topical therapies, eg, lidocaine 5% patch, may be considered for a variety of pain states and features.The major rationale for introducing adjuvants is to better balance efficacy and adverse effects. The following scenarios should prompt the use of adjuvants in clinical practice: The toxic limit of a primary analgesic has been reached. The therapeutic benefit of a primary analgesic has plateaued, eg, treatment has reached its true efficacy limit or pharmachodynamic tolerance has developed. The primary analgesic is contraindicated, eg, substance abuse, aberrant behavior, organ failure, allergy, and so forth. Subjective and qualitative symptoms demand broader coverage. Patients often convey that different medications will impart distinct analgesic benefits. Presence of disabling nonpainful complaints and need to manage symptoms such as insomnia, depression, anxiety, and fatigue that all cause worsening of the patient's quality of life and function. Physicians have also been drawn to the adjuvants secondary to new realities of clinical practice. Moreover, aversion to addiction and diversion remains a potent force that shapes prescribing profiles.
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PMID:Adjuvant analgesics. 1716 7

The cereal pathogen Fusarium graminearum threatens food and feed production worldwide. It reduces the yield and poisons the remaining kernels with mycotoxins, notably deoxynivalenol (DON). We analyzed the importance of gamma-aminobutanoic acid (GABA) metabolism for the life cycle of this fungal pathogen. GABA metabolism in F. graminearum is partially regulated by the global nitrogen regulator AreA. Genetic disruption of the GABA shunt by deletion of two GABA transaminases renders the pathogen unable to utilize the plant stress metabolites GABA and putrescine. The mutants showed increased sensitivity against oxidative stress, GABA accumulation in the mycelium, downregulation of two key enzymes of the TCA cycle, disturbed potential gradient in the mitochondrial membrane and lower mitochondrial oxygen consumption. In contrast, addition of GABA to the wild type resulted in its rapid turnover and increased mitochondrial steady state oxygen consumption. GABA concentrations are highly upregulated in infected wheat tissues. We conclude that GABA is metabolized by the pathogen during infection increasing its energy production, whereas the mutants accumulate GABA intracellularly resulting in decreased energy production. Consequently, the GABA mutants are strongly reduced in virulence but, because of their DON production, are able to cross the rachis node.
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PMID:Disruption of the GABA shunt affects mitochondrial respiration and virulence in the cereal pathogen Fusarium graminearum. 2630 50

Schisandra chinensis fruits are a famous traditional Chinese medicine to treat all kinds of fatigue. This study aimed to investigate the therapeutic effect and metabolic mechanism of a polysaccharide (SCP) from Schisandra chinensis fruits on chronic fatigue syndrome (CFS). SCP was isolated and the physicochemical properties were analyzed. A CFS model of rats was established and the urinary metabonomic studies were performed using gas chromatography time-of-flight mass spectrometry (GC-TOF-MS) in combination with multivariate statistical analysis. The results showed that SCP is a protein-bound polysaccharide. The amino acid composition of SCP consisted of 12 amino acids. The growth and the behaviors of the rats in the CFS model group were worse than those in the control group and improved after SCP treatment. Analysis of the GC-TOF-MS revealed that twelve metabolites were significantly changed, and six metabolites were oppositely and significantly changed after the SCP treatment. The TCA cycle metabolic pathways and the alanine, aspartate and glutamate metabolism were identified as significant metabolic pathways involved with SCP. The therapeutic mechanism of SCP against CFS was partially due to the restoration of these disturbed pathways.
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PMID:Metabolic mechanism of a polysaccharide from Schisandra chinensis to relieve chronic fatigue syndrome. 2754 8

In electroencephalography (EEG)-based emotion recognition systems, the distribution between the training samples and the testing samples may be mismatched if they are sampled from different experimental sessions or subjects because of user fatigue, different electrode placements, varying impedances, etc. Therefore, it is difficult to directly classify the EEG patterns with a conventional classifier. The domain adaptation method, which is aimed at obtaining a common representation across training and test domains, is an effective method for reducing the distribution discrepancy. However, the existing domain adaptation strategies either employ a linear transformation or learn the nonlinearity mapping without a consistency constraint; they are not sufficiently powerful to obtain a similar distribution from highly non-stationary EEG signals. To address this problem, in this paper, a novel component, called the subspace alignment auto-encoder (SAAE), is proposed. Taking advantage of both nonlinear transformation and a consistency constraint, we combine an auto-encoder network and a subspace alignment solution in a unified framework. As a result, the source domain can be aligned with the target domain together with its class label, and any supervised method can be applied to the new source domain to train a classifier for classification in the target domain, as the aligned source domain follows a distribution similar to that of the target domain. We compared our SAAE method with six typical approaches using a public EEG dataset containing three affective states: positive, neutral, and negative. Subject-to-subject and session-to-session evaluations were performed. The subject-to-subject experimental results demonstrate that our component achieves a mean accuracy of 77.88% in comparison with a state-of-the-art method, TCA, which achieves 73.82% on average. In addition, the average classification accuracy of SAAE in the session-to-session evaluation for all the 15 subjects in a dataset is 81.81%, an improvement of up to 1.62% on average as compared to the best baseline TCA. The experimental results show the effectiveness of the proposed method relative to state-of-the-art methods. It can be concluded that SAAE is a useful and effective tool for decreasing domain discrepancy and reducing performance degradation across subjects and sessions in the EEG-based emotion recognition field.
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PMID:Unsupervised domain adaptation techniques based on auto-encoder for non-stationary EEG-based emotion recognition. 2781 Jun 26


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