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

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 technique of nuclear magnetic resonance (n.m.r.) is briefly described to illustrate its use for estimating metabolite levels in vivo. Our studies of fatigue in anaerobic frog muscle at 4 degree C are described in relation to (a) force development, (b) speed of relaxation and (c) the switching on and off of glycolysis. Both (a) and (b) are closely related, though in different ways, to the concentrations of key metabolites. In contrast, (c) is not related to metabolite levels as such but to the events of contraction and relaxation. A special n.m.r. technique (saturation transfer) has been used to study the creatine kinase system in vivo. The results show that this system is highly active and is in equilibrium in resting muscle. The free [ADP] is consequently only a small fraction of that found by analysis of muscle extracts. Studies of human power production as a function of duration of exercise also indicate that it is shortage of chemical fuel that brings short- and medium-term exercise (0.1-10 min) to a halt. It is proposed to extend n.m.r. methods to human subjects in the near future. A working hypothesis to account for fatigue is suggested in which both the contractile system and the activating system play a part.
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PMID:Shortage of chemical fuel as a cause of fatigue: studies by nuclear magnetic resonance and bicycle ergometry. 691 67

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. We have used phosphorus nuclear magnetic resonance (31P NMR) to study muscular fatigue in anaerobic amphibian muscle. In this paper the biochemical and energetic changes that result from a series of tetani are related to the decrease in rate constant (1/tau) for the final, exponential, phase of relaxation. 2. Using 31P NMR we have measured the concentrations of phosphocreatine (PCr), inorganic phosphate (Pi) and ATP as well as the internal pH. From our measurements we have calculated [creatine], [free ADP], the free-energy change (more precisely, the affinity A = -dG/d xi) for ATP hydrolysis and the rates of lactic acid production and of ATP hydrolysis. 3. We have found that 1/tau, the rate constant of relaxation, is correlated with each of the following, independently of the pattern of stimulation: isometric force production, all of the measured or calculated metabolite levels, pH and dG/d xi. 4. There is a clear dependence upon the pattern of stimulation of the relation between 1/tau and each of the following: total duration of the experiment, number of contractions, rate of lactic acid production and rate of ATP hydrolysis. 5. The rate of relaxation is linearly related to [PCr], [creatine], [Pi] and dG/d xi. It is nonlinearly related to isometric force, [ATP], [H+] and rate of ATP hydrolysis. 6. We conclude that the change in 1/tau, like that of isometric force, depends upon metabolic factors, and not upon any independent changes in the activation or deactivation of contraction. We suggest that 1/tau may depend upon the free-energy change for ATP hydrolysis which in turn may be related to the rate of Ca2+ uptake into the sarcoplasmic reticulum.
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PMID:Mechanical relaxation rate and metabolism studied in fatiguing muscle by phosphorus nuclear magnetic resonance. 696 88

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

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 phosphate 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 conentrations 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). 741 22

Muscle performance declines during prolonged and intense activity; important components are a reduction in force production and shortening velocity and a prolongation of relaxation. In this review we consider how the changes in metabolites (particularly H+, inorganic phosphate (Pi), ATP and ADP) and changes in sarcoplasmic reticulum Ca2+ release lead to the observed changes in force, shortening velocity and relaxation. The reduced force is caused by a combination of reduced maximum force-generating capacity, reduced myofibrillar Ca2+ sensitivity and reduced Ca2+ release. The reduced maximum force and Ca2+ sensitivity are largely explained by the effects of H+ and Pi that have been observed in skinned fibres. At least three different forms of reduced Ca2+ release can be recognized but the mechanisms involved are incompletely understood. The reduced shortening velocity can be partly explained by the effects of H+ that have been observed in skinned fibres. In addition it is proposed that ADP, which depresses shortening velocity, increases during contractions to a level that is considerably higher than existing measurements suggest. Changes in Ca2+ release are probably unimportant for the reduced shortening velocity. The prolongation of relaxation can arise both from slowing of the rate of decline of myoplasmic calcium concentration and from slowing of cross-bridge detachment rates. A method of analysis which separates these components is described. The increase in H+ and the other metabolite changes during fatigue can independently affect both components. Finally we show that reduced force, shortening velocity and slowed relaxation all contribute to the decline in muscle performance during a working cycle in which the muscle first shortens actively and then is stretched passively by an antagonist muscle.
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PMID:Muscle cell function during prolonged activity: cellular mechanisms of fatigue. 757 93


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