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

Although fatigue is a well-known phenomenon and the phrase "exercised until exhaustion" is commonly understood, there is no unequivocal agreement on the fundamental nature of the fatigue process. Ammonia was linked to the development of fatigue as early as 1922, when ammonia production was observed from stimulated nerve and the question whether there could be a relationship between ammonia production and the muscle activity was raised. The immediate source of ammonia from muscle appears to be a result of the deamination of AMP and is more apparent in fast-twitch than in slow-twitch fibers. More recently, increases in blood ammonia levels have been reported in rats after swimming and in humans after arm work, maximal cycle ergometry, and treadmill exercise. Elevated blood ammonia has also been linked to a surprising variety of functional and metabolic neurological disturbances other than exercise and fatigue, including the development of hepatic coma, convulsions from ammonia toxicity precipitated by high-pressure oxygen breathing, epileptic seizures, and decreased neuronal excitability. In addition, a number of genetic disorders (inborn errors in metabolism, or IEMs) are characterized by elevated blood ammonia concentrations. Symptoms of neural disability in all of the above conditions have been related to the concentration of ammonia in blood. Although these studies do not relate to exercise or fatigue directly, it is conceivable that our understanding of the effect of high concentrations of blood ammonia in these clinical conditions may provide valuable insight into the effect of ammonia during exercise. This paper reviews the effect of ammonia production during exercise and other conditions upon purposeful activity and the development of fatigued states.
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PMID:Ammonia metabolism in exercise and fatigue: a review. 634 52

Uremia is associated with decreased brain oxygen consumption in humans and with decreased brain energy consumption in rodent models of acute renal failure. We measured the levels of high-energy phosphates and glycolytic intermediates in the brain of dogs with acute or chronic renal failure. We used methods of rapid brain tissue fixation that trap these labile metabolites at their in vivo levels. Creatine phosphate, ATP, and glucose were normal in the brain of animals with renal failure, indicating a normal brain energy reserve. The brain energy charge, which is the fraction of the total adenine nucleotide pool that contains high-energy phosphates, (ATP + 1/2ADP)/(ATP + ADP + AMP), was also normal despite an 8% decrease in the total adenine nucleotide pool. Mild hypoxia failed to alter the level of any of these metabolites. The brain redox state, (NAD+)/(NADH), was normal to high in acute renal failure, suggesting that oxygen supply was not limiting oxygen consumption. In the face of normal brain energy reserves, energy charge, and redox state, the decreased energy consumption of uremic brain probably results from decreased demand rather than limited supply.
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PMID:Uremic encephalopathy: role of brain energy metabolism. 647 28

Hypertensive disease is known to increase the risks in connection with acute changes in blood pressure due to the presence of pronounced structural as well as functional changes in the cardiovascular system. In the present study the metabolic consequences of fixed haemorrhagic hypotension [mean arterial pressure (MAP) 70 and 45 mmHg] were studied in spontaneously hypertensive (SHR) and in normotensive rats (WKY). Blood gases and acid-base balance, blood glucose, liver (ATP, glucose, lactate) and brain (ATP, ADP, AMP, CP, glucose, lactate) metabolites were determined in unbled animals and after 35 min hypotension in bled animals. In the liver haemorrhage to MAP 70 mmHg resulted in a 70% reduction of the ATP content in SHR while that in WKY remained unchanged. At MAP 45 mmHg reduced liver ATP levels (35% reduction) were observed in WKY as well. In the brain metabolic changes indicative of tissue ischaemia (reduced CP, increased AMP and lactate, decreased energy charge potential) were present only in SHR at MAP 45 mmHg. The more pronounced metabolic disturbances in SHR than in WKY indicate that blood loss is more deleterious for the hypertensive individual.
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PMID:Effects of haemorrhagic hypotension on brain and liver metabolism in normotensive (WKY) and spontaneously hypertensive rats (SHR). 668 Oct 40

To assess the role of the purine nucleotide cycle in human skeletal muscle function, we evaluated 10 patients with AMP deaminase deficiency (myoadenylate deaminase deficiency; MDD). 4 MDD and 19 non-MDD controls participated in an exercise protocol. The latter group was composed of a patient cohort (n = 8) exhibiting a constellation of symptoms similar to those of the MDD patients, i.e., postexertional aches, cramps, and pains; as well as a cohort of normal, unconditioned volunteers (n = 11). The individuals with MDD fatigued after performing only 28% as much work as their non-MDD counterparts. Muscle biopsies were obtained from the four MDD patients and the eight non-MDD patients at rest and following exercise to the point of fatigue. Creatine phosphate content fell to a comparable extent in the MDD (69%) and non-MDD (52%) patients at the onset of fatigue. Following exercise the 34% decrease in ATP content of muscle from the non-MDD subjects was significantly greater than the 6% decrease in ATP noted in muscle from the MDD patients (P = 0.048). Only one of four MDD patients had a measurable drop in ATP compared with seven of eight non-MDD patients. At end-exercise the muscle content of inosine 5'-monophosphate (IMP), a product of AMP deaminase, was 13-fold greater in the non-MDD patients than that observed in the MDD group (P = 0.008). Adenosine content of muscle from the MDD patients increased 16-fold following exercise, while there was only a twofold increase in adenosine content of muscle from the non-MDD patients (P = 0.028). Those non-MDD patients in whom the decrease in ATP content following exercise was measurable exhibited a stoichiometric increase in IMP, and total purine content of the muscle did not change significantly. The one MDD patient in whom the decrease in ATP was measurable, did not exhibit a stoichiometric increase in IMP. Although the adenosine content increased 13-fold in this patient, only 48% of the ATP catabolized could be accounted for by the combined increases of adenosine, inosine, hypoxanthine, and IMP. Studies performed in vitro with muscle samples from seven MDD and seven non-MDD subjects demonstrated that ATP catabolism was associated with a fivefold greater increase in IMP in non-MDD muscle. There were significant increases in AMP and ADP content of the muscle from MDD patients following ATP catabolism in vitro, while there was no detectable increase in AMP or ADP in non-MDD muscle. Adenosine content of MDD muscle increased following ATP catabolism, but there was no detectable increase in adenosine content of non-MDD muscle following ATP catabolism in vitro. These studies demonstrate that AMP deaminase deficiency leads to reduced entry of adenine nucleotides into the purine nucleotide cycle during exercise. We postulate that the resultant disruption of the purine nucleotide cycle accounts for the muscle dysfunction observed in these patients.
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PMID:Myoadenylate deaminase deficiency. Functional and metabolic abnormalities associated with disruption of the purine nucleotide cycle. 670 1

Previous observations have shown that in human subjects with malnutrition and after prolonged fasting, there are characteristic changes in the force-frequency response, relaxation rate and power of muscle during a 30 s stimulus (fatigue). In order to characterize these findings under carefully controlled conditions, in different types of muscle and to correlate them with changes in muscle structure, composition and biochemical status, we developed an animal model in rats. In this model, nutrient restriction, both after an acute fast and after chronic hypocaloric feeding, resulted in: (a) loss of force during high frequency stimulation but preservation of contraction-relaxation characteristics during low frequency stimulation; (b) slower muscle relaxation rate at high frequency stimulation; (c) increased muscle fatiguability at high frequency stimulation. Measurements of muscle enzymes showed that acute fasting resulted in a reduced content of glycolytic enzymes, but preservation of oxidative enzymes, while chronic hypocaloric dieting resulted in a reduction in both classes of enzyme. There was no significant change in ATP, AMP or energy charge, or in intracellular sodium, potassium and magnesium levels. Creatine phosphate was normal in acutely fasted animals but low in those fed hypocalorically. By contrast, increased intracellular calcium and ADP levels were seen in both fasted and hypocalorically fed animals. These findings suggest that subtle disturbances of intracellular energy states with altered calcium flux may be of importance in the genesis of muscle dysfunction caused by malnutrition.
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PMID:The effect of fasting and hypocaloric diets on the functional and metabolic characteristics of rat gastrocnemius muscle. 674 88

The basis for skeletal muscle dysfunction in phosphate-deficient patients and animals is not known, but it is hypothesized that intracellular phosphate deficiency leads to a defect in ATP synthesis. To test this hypothesis, changes in muscle function and nucleotide metabolism were studied in an animal model of hypophosphatemia. Mice were made hypophosphatemic through restriction of dietary phosphate intake. Gastrocnemius function was assessed in situ by recording isometric tension developed after stimulation of the nerve innervating this muscle. Changes in purine nucleotide, nucleoside, and base content of the muscle were quantitated at several time points during stimulation and recovery. Serum concentration and skeletal muscle content of phosphorous are reduced by 55 and 45%, respectively, in the dietary restricted animals. The gastrocnemius muscle of the phosphate-deficient mice fatigues more rapidly compared with control mice. ATP and creatine phosphate content fall to a comparable extent during fatigue in the muscle from both groups of animals; AMP, inosine, and hypoxanthine (indices of ATP catabolism) appear in higher concentration in the muscle of phosphate-deficient animals. Since total ATP use in contracting muscle is closely linked to total developed tension, we conclude that the comparable drop in ATP content in association with a more rapid loss of tension is best explained by a slower rate of ATP synthesis in the muscle of phosphate-deficient animals. During the period of recovery after muscle stimulation, ATP use for contraction is minimal, since the muscle is at rest. In the recovery period, ATP content returns to resting levels more slowly in the phosphate-deficient than in the control animals. In association with the slower rate of ATP repletion, the precursors inosine monophosphate and AMP remain elevated for a longer period of time in the muscle of phosphate-deficient animals. The slower rate of ATP repletion correlates with delayed return of normal muscle contractility in the phosphate-deficient mice. These studies suggest that the slower rate of repletion of the ATP pool may be the consequence of a slower rate of ATP synthesis and this is in part responsible for the delayed recovery of normal muscle contractility.
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PMID:Defective adenosine triphosphate synthesis. An explanation for skeletal muscle dysfunction in phosphate-deficient mice. 687 57

During vigorous, strong contractions there is a rapid decline in the mechanical output or tension development in skeletal muscle. Several studies have indicated that this rapid decline in force development (often referred to as fatigue), is caused by metabolic changes in the muscles. During brief intense exercise there is a rapid breakdown of phosphocreatine and glycogen and a concomitant increase in the lactate and hydrogen ion concentration. The muscle lactate concentration is increased from about 1-2 mmol kg-1 wet weight at rest before exercise to approximately 25-30 mmol kg-1 wet weight immediately after intensive brief exercise to exhaustion. The muscle pH (i.e. the pH of muscle homogenates) falls from about 7.0 at rest to approximately 6.4 at exhaustion. The changes in the concentrations of ATP, ADP, and AMP are small. It is suggested that the changes in intracellular pH might affect the force generation of skeletal muscle by two different mechanisms: (1) The fall in intracellular pH reduces the activity of key enzymes in glycolysis, thus reducing the rate of ATP resynthesis, and (2) the increased hydrogen ion concentration has a direct effect on the contractile processes, thus reducing the rate of ATP utilization. It is suggested that the increased hydrogen ion concentration might be the common regulator for the maximal rate at which ATP is being utilized and the maximal rate at which it is being resynthesized.
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PMID:Effect of metabolic changes on force generation in skeletal muscle during maximal exercise. 691 79

1 (+)-Octanoylcarnitine, a potent inhibitor of fatty acid oxidation, was infused intraportally into rabbits after 70% hepatectomy, and its effects on the rate of deoxyribonucleic acid (DNA) synthesis were examined. 2. The rate of DNA synthesis was markedly enhanced 48 h after hepatectomy. At this time, synthesis was decreased significantly by (+)-octanoylcarnitine. 3. It is suggested that fatty acid oxidation contributes to enhanced hepatic regeneration by elevating the decreased energy charge level [(ATP + 0.5ADP)/(ATP + ADP + AMP)] of the remnant liver.
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PMID:Effects of (+)-octanoylcarnitine on deoxyribonucleic acid synthesis in regenerating rabbit liver. 706 Mar 36

The effect of liver support on the adenylate energy charge (ATP + 0.5ADP)/(ATP + ADP + AMP) of the remnant liver after major hepatic resection was studied in rabbits. The present study emphasized the principle of restoring the decreased energy charge level of the remnant liver after major hepatic resection by use of an ex vivo heterologous liver cross-hemodialysis with an interposed Cuprophan membrane. The energy charge level provides the cell with a very sensitive intracellular control mechanism. Regulatory enzymes from biosynthetic sequences exhibit very little activity at low levels of energy charge, and their activities increase sharply at high-energy charge levels. The energy charge level of the remnant liver maximally decreased from the control level of 0.860 to 0.767 at 24 hours after 70% hepatectomy. The energy charge level increased from 0.767 to 0.857 after two hours of cross-hemodialysis with an interposed Cuprophan membrane between the 24-hour, 70% hepatectomized rabbit and an ex vivo pig liver with high energy charge. The above results suggest that this ex vivo pig cross-hemodialysis may be effective for biosynthesis in the regenerative processes of the remnant liver.
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PMID:The effects of heterologous liver cross-hemodialysis on adenylate energy charge of the remnant liver after major hepatic resection. 716 59

Adult male rats were exposed to 3.8-km altitude for intervals ranging from 1 h-60 d. Liver samples were taken under light ether anesthesia and were examined by enzymatic analyses. Within 1-6 h of hypoxic exposure, ATP levels decreased while ADP and AMP levels increased, producing a fall in calculated ATP/ADP and adenylate charge ratios. Concurrently, lactate/pyruvate and alpha-glycerophosphate/dihydroxyacetone phosphate ratios increased markedly. Direct measurements of cellular pyridine nucleotides indicated increased NADH/NAD and NADPH/NADP ratios. Levels of total adenosine phosphates and pyridine nucleotides decreased in a significant accompanying response. Many metabolite levels and calculated ratios returned to near-normal values within 1 week of exposure, indicating secondary intracellular adjustments to hypoxic stress; however, persistence of that stress is reflected in lactate concentrations and both substrate redox ratios. Results support and explore concepts that increased oxidation-reduction status and decreased energy status are primary events during hypoxia.
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PMID:Energy status and oxidation-reduction status in rat liver at high altitude (3.8 km). 738 68


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