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Query: UMLS:C0015672 (fatigue)
 51,768 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A review of metabolic pathways is presented, which are involved in muscular energy production during hypoxia according to recent experimental findings. By means of own exercise examinations the course of reactions providing ATP anaerobically in the muscles of limbs with poor circulation is analysed. Therefore, the arteriovenous differences in the concentrations of lactate, pyruvate, ammonia, hypoxanthine and alanine in the femoral blood of patients with stage II AOD were determined. In addition, the intracellular phosphorus compounds ATP, PCr and Pi as well as the tissue pH were measured noninvasively in the calf muscles using 31P magnetic resonance spectroscopy. The results give evidence for marked activation of the creatine kinase reaction, of glycolysis, of the myokinase reaction and of the purine nucleotide cycle in the ischaemic musculature at loads of short duration, which are in total sufficient to maintain the concentration of ATP even during claudication pain. In spite of salvage pathways like alanine formation, the end products of these "emergency reactions", Pi, H+ and NH4+, accumulate and exert deleterious cytotoxic effects, which are thought to be responsible for rapid muscle fatigue and claudication pain in PAOD.
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PMID:[Regulation of ischemic muscle metabolism in peripheral arterial occlusive disease]. 267 1

The incidence and extent of cerebral damage following open-heart surgery were prospectively investigated in 103 patients, using clinical assessment, psychometry, adenylate kinase analysis in cerebrospinal fluid (CSF-AK) and computed tomography (CT) of the brain. The surgical mortality was 1.9%. Clinically there was obvious cerebral dysfunction in four cases, subtle evidence of brain damage (mainly undue fatigue) in 16 and no evidence in 81 cases. In the 16 patients the mean CSF-AK was substantially increased (0.122 U/l) and the psychometric performance distinctly impaired (-12 points) postoperatively; in the 81 patients the figures were 0.55 U/l and -3.4. Psychometrically, 60% of the patients showed cerebral dysfunction, which was pronounced in 16%. CSF-AK analysis indicated cerebral damage as absent or trival in 45%, moderate in 33% and marked in 22%. CT revealed postoperative cerebral infarction in two cases. Results from the various methods showed reasonable correlation, but also considerable overlap. Open-heart surgery thus can cause brain damage additional to that neurologically discernible. Fatigue is an important sign in this context. In research on postoperative brain damage, the relative insensitivity of routine neurologic investigation calls for supplementary, refined methods.
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PMID:Cerebral damage during open-heart surgery. Clinical, psychometric, biochemical and CT data. 349 46

During muscular fatigue two metabolites, hydrogen ions (H+) and inorganic phosphate (Pi), increase in concentration. The effect of increase in [H+] has been modeled mathematically for a system containing creatine kinase (EC 2.7.3.2), adenylate kinase (EC 2.7.4.3), and the appropriate concentrations of their substrates. Assuming that no other equilibrium reactions are involved, the result of acidification should be a useful increase in the ratio [ATP]/[ADP]. It is also shown by a reanalysis of earlier 31P NMR studies that the observed combination of increased [H+] and increased [Pi] leads to an increase in the monobasic phosphate concentration [Pi-] that is inversely proportional to the force of contraction. This suggests that Pi- may be a direct inhibitor of the actomyosin ATPase system.
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PMID:Muscular fatigue: effects of hydrogen ions and inorganic phosphate. 353 90

The production of AMP by adenylate kinase (AK) and subsequent deamination by AMP deaminase limits ADP accumulation during conditions of high-energy demand in skeletal muscle. The goal of this study was to investigate the consequences of AK deficiency (-/-) on adenine nucleotide management and whole muscle function at high-energy demands. To do this, we examined isometric tetanic contractile performance of the gastrocnemius-plantaris-soleus (GPS) muscle group in situ in AK1(-/-) mice and wild-type (WT) controls over a range of contraction frequencies (30-120 tetani/min). We found that AK1(-/-) muscle exhibited a diminished inosine 5'-monophosphate formation rate (14% of WT) and an inordinate accumulation of ADP ( approximately 1.5 mM) at the highest energy demands, compared with WT controls. AK-deficient muscle exhibited similar initial contractile performance (521 +/- 9 and 521 +/- 10 g tension in WT and AK1(-/-) muscle, respectively), followed by a significant slowing of relaxation kinetics at the highest energy demands relative to WT controls. This is consistent with a depressed capacity to sequester calcium in the presence of high ADP. However, the overall pattern of fatigue in AK1(-/-) mice was similar to WT control muscle. Our findings directly demonstrate the importance of AMP formation and subsequent deamination in limiting ADP accumulation. Whole muscle contractile performance was, however, remarkably tolerant of ADP accumulation markedly in excess of what normally occurs in skeletal muscle.
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PMID:Skeletal muscle contractile performance and ADP accumulation in adenylate kinase-deficient mice. 1565 12

Metabolic control within skeletal muscle is designed to limit ADP accumulation even during conditions where ATP demand is out of balance with ATP synthesis. This is accomplished by the reactions of adenylate kinase (AK; ADP+ADP <--> AMP+ATP) and AMP deaminase (AMP+H(2)O --> NH(3)+IMP), which limit ADP accumulation under these conditions. The purpose of this study was to determine whether AK deficiency (AK(-/-)) would result in sufficient ADP accumulation to be visible using (31)P-NMRS during the high energy demands of frequent in situ tetanic contractions. To do this we examined the high-energy phosphates of the gastrocnemius muscle in the knockout mouse with AK1(-/-) and wild-type (WT) control muscle over the course of 64 rapid (2/s) isometric tetanic contractions. Near-complete depletion of phosphocreatine was apparent after 16 contractions in both groups. By approximately 40 contractions, ADP was clearly visible in AK1(-/-) muscle. This transient concentration of the NMR visible free ADP was estimated to be approximately 1.7 mM, and represents the first time free ADP has been directly measured in contracting skeletal muscle. Such an increase in free ADP is severalfold greater than previously thought to occur. This large accumulation of free ADP also represents a significant reduction in energy available from ATP, and has implications on cellular processes that depend on a high yield of energy from ATP such as calcium sequestration. Remarkably, the AK1(-/-) and WT muscles exhibited similar fatigue profiles. Our findings suggest that skeletal muscle is surprisingly tolerant to a large increase in ADP and by extension, a decline in energy from ATP.
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PMID:31P-NMR observation of free ADP during fatiguing, repetitive contractions of murine skeletal muscle lacking AK1. 1568 8

In silico studies carried out by using a computer model of oxidative phosphorylation and anaerobic glycolysis in skeletal muscle demonstrated that deamination of AMP to IMP during heavy short term exercise and/or hypoxia lessens the acidification of myocytes. The concerted action of adenylate kinase and AMP deaminase, leading to a decrease in the total adenine nucleotide pool, constitutes an additional process consuming ADP and producing ATP. It diminishes the amount of ADP that must be converted to ATP by other processes in order to meet the rate of ADP production by ATPases (because the adenylate kinase + AMP deaminase system produces only 1 ATP per 2 ADPs used, ATP consumption is not matched by ATP production, and the reduction of the total adenine nucleotide pool occurs mostly at the cost of [ATP]). As a result, the rate of ADP consumption by other processes may be lowered. This effect concerns mostly ADP consumption by anaerobic glycolysis that is inhibited by AMP deamination-induced decrease in [ADP] and [AMP], and not oxidative phosphorylation, because during heavy exercise and/or hypoxia [ADP] is significantly greater than the Km value of this process for ADP. The resultant reduction of proton production by anaerobic glycolysis enables us to delay the termination of exercise because of fatigue and/or to diminish cell damage.
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PMID:AMP deamination delays muscle acidification during heavy exercise and hypoxia. 1631 16

Cancer cachexia is a highly debilitating paraneoplastic disease observed in more than 50% of patients with advanced cancers and directly contributes to 20% of cancer deaths. Loss of skeletal muscle is a defining characteristic of patients with cancer cachexia and is associated with poor survival. The present study reveals the involvement of a myogenic transcription factor Myocyte Enhancer Factor (MEF) 2C in cancer-induced skeletal muscle wasting. Increased skeletal muscle mRNA expression of Suppressor of Cytokine Signaling (Socs) 3 and the IL-6 receptor indicative of active IL-6 signaling was seen in skeletal muscle of mice bearing the Colon 26 (C26) carcinoma. Loss of skeletal muscle structural integrity and distorted mitochondria were also observed using electron microscopy. Gene and protein expression of MEF2C was significantly downregulated in skeletal muscle from C26-bearing mice. MEF2C gene targets myozenin and myoglobin as well as myokinase were also altered during cachexia, suggesting dysregulated oxygen transport capacity and ATP regeneration in addition to distorted structural integrity. In addition, reduced expression of calcineurin was observed which suggested a potential pathway of MEF2C dysregulation. Together, these effects may limit sarcomeric contractile ability and also predispose skeletal muscle to structural instability; associated with muscle wasting and fatigue in cachexia.
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PMID:Disruption of MEF2C signaling and loss of sarcomeric and mitochondrial integrity in cancer-induced skeletal muscle wasting. 2236 33

Germline mutations in cellular-energy associated genes have been shown to lead to various monogenic disorders. Notably, mitochondrial disorders often impact skeletal muscle, brain, liver, heart, and kidneys, which are the body's top energy-consuming organs. However, energy-related dysfunctions have not been widely seen as causes of common diseases, although evidence points to such a link for certain disorders. During acute energy consumption, like extreme exercise, cells increase the favorability of the adenylate kinase reaction 2-ADP -> ATP+AMP by AMP deaminase degrading AMP to IMP, which further degrades to inosine and then to purines hypoxanthine -> xanthine -> urate. Thus, increased blood urate levels may act as a barometer of extreme energy consumption. AMP deaminase deficient subjects experience some negative effects like decreased muscle power output, but also positive effects such as decreased diabetes and improved prognosis for chronic heart failure patients. That may reflect decreased energy consumption from maintaining the pool of IMP for salvage to AMP and then ATP, since de novo IMP synthesis requires burning seven ATPs. Similarly, beneficial effects have been seen in heart, skeletal muscle, or brain after treatment with allopurinol or febuxostat to inhibit xanthine oxidoreductase, which catalyzes hypoxanthine -> xanthine and xanthine -> urate reactions. Some disorders of those organs may reflect dysfunction in energy-consumption/production, and the observed beneficial effects related to reinforcement of ATP re-synthesis due to increased hypoxanthine levels in the blood and tissues. Recent clinical studies indicated that treatment with xanthine oxidoreductase inhibitors plus inosine had the strongest impact for increasing the pool of salvageable purines and leading to increased ATP levels in humans, thereby suggesting that this combination is more beneficial than a xanthine oxidoreductase inhibitor alone to treat disorders with ATP deficiency.
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PMID:Shortage of Cellular ATP as a Cause of Diseases and Strategies to Enhance ATP. 3083 73