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

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

The effect of prior glycogen depletion on glycolysis [flux through phosphofructokinase (PFK)] and inosine monophosphate (IMP) formation in human skeletal muscle has been investigated. Eight subjects cycled at a work load calculated to elicit 95% of maximal O2 uptake on two occasions, the first to fatigue [5.5 +/- 0.3 (SE) min] and the second at the same workload and for the same duration as the first. Before the first experiment, muscle glycogen stores were lowered by a combination of exercise and diet. Before the second experiment, muscle glycogen stores were supercompensated. In the low-glycogen (LG) state muscle glycogen decreased from 201 +/- 31 mmol glucosyl units/kg dry wt at rest to 105 +/- 28 after exercise, and in the high-glycogen (HG) state from 583 +/- 40 to 460 +/- 49. The accumulation of fructose 6-phosphate (F-6-P; activator of PFK) during exercise was markedly attenuated in the LG state (P less than 0.01), whereas lactate accumulation in muscle was similar between treatments, suggesting that muscle pH was also similar. Glycolysis (estimated from glycogenolysis minus accumulation of hexose monophosphates) was not measurably different between treatments (LG = 88 +/- 17, HG = 106 +/- 43 mmol/kg dry wt; P greater than 0.05). IMP was significantly greater in the LG state after exercise (3.63 +/- 0.85 vs. 1.97 +/- 0.44 mmol/kg dry wt; P less than 0.05). It is concluded that decreased glycogen availability does not measurably alter the rate of muscle glycolysis during intense exercise. It is hypothesized that the attenuated increase in F-6-P in the LG state, which should theoretically decrease glycolysis, is compensated for by increases in free ADP and AMP (activators of PFK) at the enzymatic site during the contraction phase. The greater increase in IMP in the LG state is consistent with this hypothesis, since ADP and AMP are also activators of AMP deaminase.
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PMID:Role of glycogen in control of glycolysis and IMP formation in human muscle during exercise. 205 62

Eight healthy men cycled at a work load corresponding to approximately 70% of maximal O2 uptake (VO2max) to fatigue (exercise I). Exercise to fatigue at the same work load was repeated after 75 min of rest (exercise II). Exercise duration averaged 65 and 21 min for exercise I and II, respectively. Muscle (quadriceps femoris) content of glycogen decreased from 492 +/- 27 to 92 +/- 20 (SE) mmol/kg dry wt and from 148 +/- 17 to 56 +/- 17 (SE) mmol/kg dry wt during exercise I and II, respectively. Muscle and blood lactate were only moderately increased during exercise. The total adenine nucleotide pool (TAN = ATP + ADP + AMP) decreased and inosine 5'-monophosphate (IMP) increased in the working muscle during both exercise I (P less than 0.001) and II (P less than 0.01). Muscle content of ammonia (NH3) increased four- and eight-fold during exercise I and II, respectively. The working legs released NH3, and plasma NH3 increased progressively during exercise. The release of NH3 at the end of exercise II was fivefold higher than that at the same time point in exercise I (P less than 0.001, exercise I vs. II). It is concluded that submaximal exercise to fatigue results in a breakdown of the TAN in the working muscle through deamination of AMP to IMP and NH3. The relatively low lactate levels demonstrate that acidosis is not a necessary prerequisite for activation of AMP deaminase. It is suggested that the higher average rate of AMP deamination during exercise II vs. exercise I is due to a relative impairment of ATP resynthesis caused by the low muscle glycogen level.
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PMID:Adenine nucleotide degradation in human skeletal muscle during prolonged exercise. 275 35

The changes in ammonia (NH3) and amino acid contents in human skeletal muscle during isometric exercise (2/3 maximal voluntary contraction force) to fatigue have been investigated. Biopsies from musculus quadriceps femoris were obtained at rest, fatigue, and 1 and 4 min recovery. Muscle NH3 (n = 9) increased from 1.3 +/- 0.3 (mean +/- SE) mmol/kg dry muscle (dm) at rest to 3.6 +/- 0.6 at fatigue (P less than 0.01) and remained elevated during recovery, whereas the lactate increase after contraction decreased rapidly during recovery. Total adenine nucleotide (TAN) content decreased from 28.7 +/- 0.5 mmol/kg dm at rest to 25.1 +/- 0.6 at fatigue (P less than 0.001). Muscle glutamine did not change after contraction (P greater than 0.05), whereas glutamate decreased (P less than 0.001), and alanine increased (P less than 0.001). In vivo AMP deaminase activity (measured by the rate of TAN decrease) was positively correlated with the percentage of fast-twitch fibers (r = 0.92; P less than 0.001) and the ATP turnover rate (r = 0.75; P less than 0.001) but was not related to the muscle lactate content (r = 0.27; P greater than 0.05). Phosphocreatine decreased to 6.1 +/- 0.7 mmol/kg dm (range = 1-11) after contraction. It is concluded that during exercise activation of AMP deaminase in vivo occurs when a high ATP turnover rate is coupled with a low phosphocreatine level, muscle pH is of minor importance for direct activation of AMP deaminase in vivo, and increases in NH3 do not have an important influence on glycolysis.
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PMID:Muscle ammonia metabolism during isometric contraction in humans. 287 18

Rat slow-twitch muscle, in contrast to fast-twitch muscle, maintains its ATP content near normal during intense stimulation conditions that produce rapid fatigue. An extensive depletion of adenine nucleotide content by the deamination of AMP to IMP + NH3, typical of fast-twitch muscle, does not occur. We evaluated whether this response of slow-twitch muscle could be simply due to failure of synaptic transmission or related to cellular conditions influencing enzyme activity. Stimulation of soleus muscles in situ via the nerve or directly in the presence of curare at 120 tetani/min for 3 min resulted in extensive fatigue but normal ATP contents. Thus the lack of ATP depletion must be related to cellular events distal to neuromuscular transmission. Even nerve and direct muscle stimulation (with curare) during ischemia did not cause a large depletion of ATP or a large elevation of lactate content (12.0 +/- 0.7 mumol/g), even though the decline in tension was essentially complete. However, if the same tension decline during ischemia was prolonged by stimulating for 10 min at 12 tetani/min a large decrease in ATP (2.24 +/- 0.09 mumol/g) and increase in IMP (2.47 +/- 0.16 mumol/g) and lactate (30.4 +/- 2.0 mumol/g) content occurred. Thus adenine nucleotide deamination to IMP can occur in slow-twitch muscle during specific contraction conditions. The cellular events leading to the activation of AMP deaminase require an intense contraction condition and may be related to acidosis caused by a high lactate content.
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PMID:ATP depletion in slow-twitch red muscle of rat. 363 Dec 51

Substrate- and co-factor-dependent kinetics of AMP deaminase were studied in normal and fatigued gastrocnemius muscles of frog. Normal muscle enzyme showed greater enzyme co-factor affinity than enzyme-substrate affinity as evinced by low Kp values. Fatigue phenomenon was found to decrease the catalytic efficiency of the enzyme by lowering the enzyme-substrate affinity more than the enzyme-co-factor affinity and enhancing activation energy values. Present study elucidates the low level of operation of adenine nucleotide deamination involving AMP-deaminase reacting-system during prolonged contractile stress.
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PMID:Variation in the catalytic potential of AMP deaminase during muscular fatigue. 616 7

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

The effects of exercise (swimming), fatigue, and recovery on the intracellular pH (pHi), energy-rich phosphates, and related metabolites were studied in the gastrocnemius muscle of common frogs (Rana temporaria) at 20 degrees C. Exercise caused a rapid decrease in the content of phosphocreatine (PCr) and a corresponding increase in that of Pi. The ATP level remained virtually constant for 1 min; its precipitous decrease during the following minute was associated with a rise in the contents of inosine 5'-monophosphate (IMP) and NH4+, indicating a marked activation of AMP deaminase. Five minutes of swimming caused severe fatigue, which was correlated with decreases in muscle PCr (-85%), ATP (-42%), and pHi (-0.8 units). Recovery appeared almost complete within 2 h, and the frogs were then induced to swim again. During the initial 10 s of this second exercise, ATP synthesis was as high as in the first exercise, but the rate decreased more rapidly between 10 and 60 s, thus indicating that repeated exercise caused increased metabolic stress. IMP formation in working muscle was not strictly correlated with the pHi or the tissue contents of Pi, AMP and ADP, although from studies in vitro AMP deaminase is known to be modulated by these parameters.
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PMID:Exercise and recovery in frog muscle: metabolism of PCr, adenine nucleotides, and related compounds. 896 11

Lack of the muscle-specific isoform of AMP deaminase (myoadenylate deaminase deficiency) can cause a metabolic myopathy, with exercise-induced muscle symptoms such as early fatigue, cramps and/or myalgia. It is the most common muscle enzyme defect in man, found in about 2-3% of all muscle biopsies. The genetic basis of the inherited defect is the nonsense mutation C34-T in the AMPD1 gene encoding myoadenylate deaminase. The mutation results in a premature stop of the enzyme synthesis. In a healthy German population, the frequency of the mutant allele was 0.1, and 1% of this population is expected to be homozygous for the mutation. In people with muscle symptoms, the allele frequency was significantly higher (0.145). The correlation between allele frequency and muscle symptoms underscores the clinical significance of this defect. However, the vast majority of homozygous subjects do not develop a metabolic myopathy. This clinical heterogeneity may be due to molecular genetic factors such as alternative splicing of the exon harbouring the mutation, or due to metabolic conditions such as pathways compensating for the defect. The real basis for the high percentage of asymptomatic homozygous subjects remains to be revealed.
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PMID:Clinical heterogeneity and molecular mechanisms in inborn muscle AMP deaminase deficiency. 921 Nov 91

The activities of adenylosuccinate synthetase, adenylosuccinate lyase, and adenosine monophosphate deaminase were measured in muscle from patients suffering from fatigue and cramps following exercise. Results denote the existence of secondary deficiencies of adenylosuccinate synthetase and/or adenylosuccinate lyase in subjects with congenital or acquired myopathies. They also suggest that searches are warranted for primary deficiencies of adenylosuccinate synthetase as a cause of exercise intolerance.
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PMID:Enzymes of the purine nucleotide cycle in muscle of patients with exercise intolerance. 948 71


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