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

Glycogenosis type V (McArdle disease) is a serious metabolic disorder with an exercise intolerance, myalgia, early fatigue and stiffness of exercising muscles, relieved++ by rest. The authors present a case report of patient with McArdle's disease, and diagnostic procedures which can be used in different diagnostic of metabolic myopathies, especially between myoadenylate deaminase deficiency and different types of gly(geno)lytic myopathies. The importance of "ischemic forearm test" and muscle biopsy is emphasized.
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PMID:[McArdle's disease]. 130 14

Experimental therapies for McArdle's disease have been directed toward increasing substrate availability to exercising muscle. Such therapies to date have proven largely unsuccessful. These include administration of isoproterenol to increase blood flow, glucagon treatment to elevate serum glucose and increased dietary fat intake. Each of these therapies also results in greater levels of unesterified fatty acids in blood. More recently, a high protein diet is suggested to provide increased amounts of amino acids which would be available as fuel sources. We hypothesize that the absence of myophosphorylase in McArdle's disease creates an imbalance between the enzymes of the redox systems that control the generation, propagation and inactivation of free radicals. This occurs because muscle cells are forced to rely more heavily on fatty acid oxidation. The resulting free radical damage to cellular components disrupts metabolic control and increases the permeability of membranes. Elevated levels of Ca2+ in the sarcoplasm activate proteases, phospholipases and other catabolic enzymes initiating muscle fatigue and cramping. Lipid peroxidation is a consequence of normal muscle activity and may occur unchecked in individuals with McArdle's disease. Continued muscle activity in the absence of a favorable nutritional environment may promote the progression of the disease by increasing susceptibility to oxidative stress.
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PMID:The role of lipid peroxidation in McArdle's disease: applications for treatment of other myopathies. 146 Nov 77

We studied plasma ammonia and exercise tolerance in six patients with McArdle's disease (myophosphorylase deficiency, type V glycogenosis) during incremental cycle ergometry. Tests were performed either in the postabsorptive state or after supplementation with branched-chain amino and 2-oxoacids and glucose. Glucose and branched-chain 2-oxoacid combined increased total work performed from control 49 +/- 22 to 80 +/- 36 kJ (P less than 0.05). Glucose alone also improved total work performed from 49 +/- 22 to 64 +/- 33 kJ (P less than 0.05). Branched-chain 2-oxoacids alone had a variable effect, and branched-chain amino acids were of no benefit. Correlations between plasma ammonia and heart rate for individual patients were r = 0.99, P less than 0.01; r = 0.95, P less than 0.01; r = 0.84, P less than 0.01; r = 0.76, P less than 0.01; r = 0.73, P less than 0.01; and r = 0.63, P less than 0.05 and between ammonia and perceived exertion for all patients combined was r = 0.70, P less than 0.0001. In two patients, correlation of ammonia with heart rate at a power output of 60 W was r = 0.91, P less than 0.001 and at 40 W was r = 0.77, P less than 0.001. We conclude that ammonia is either a mediator or a marker of the metabolic events leading to fatigue.
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PMID:Relationship between ammonia, heart rate, and exertion in McArdle's disease. 153 42

A 25-year-old female with McArdle's disease was reported. She had no characteristic symptoms for McArdle's disease such as muscle cramp and brown urine, but had general fatiguability from childhood. On examination, she showed no neurological abnormalities including muscle atrophy and weakness. On laboratory examination, serum creatinine kinase (CK) level was elevated, though serum lactic acid level remained unchanged after the ischemic forearm exercise test. Muscle biopsy from the biceps brachii showed almost completely absent phosphorylase activity both histochemically and biochemically. Thus, she was diagnosed as having McArdle's disease. The skinned fiber test of the muscle showed no enhanced Ca induced Ca release (CICR), and serum VLDL level was normal. Her 27-year-old elder brother had similar clinical symptoms and serological abnormalities and may also have McArdle's disease, although muscle biopsy was not performed. A possibility of McArdle's disease should be considered when we encounter a patient who has only general fatigue and high serum CK level.
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PMID:[McArdle's disease without typical symptoms]. 208 31

Five patients with McArdle's disease entered a double-blind, placebo-controlled, cross-over study of dantrolene sodium. None of the patients experienced beneficial effect of dantrolene sodium medication. Each patient performed 2 exercise tests. Surface EMG during exercise tests without medication showed a temporary increase in EMG activity during the adaptation phase. Quite unexpectedly however, in view of the negative clinical results, this electrophysiological manifestation of muscle fatigue during the adaptation phase diminished or disappeared in all patients investigated when dantrolene sodium was used.
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PMID:Dantrolene sodium does influence the second-wind phenomenon in McArdle's disease. Electrophysiological evidence during exercise in a double-blind placebo-controlled, cross-over study in 5 patients. 208 28

Two patients with muscle phosphorylase deficiency [McArdle's disease (McA)] were studied during bicycle exercise at 40 (n = 2) and 60 W (n = 1). Peak heart rate was 170 and 162 beats/min, corresponding to approximately 90% of estimated maximal heart rate. Muscle samples were taken at rest and immediately after exercise from the quadriceps femoris. Lactate content remained low in both muscle and blood. Acetylcarnitine, which constitutes a readily available form of acetyl units and thus a substrate for the tricarboxylic acid cycle, was very low in McA patients both at rest and during exercise, corresponding to approximately 17 and 11%, respectively, of that in healthy subjects. Muscle NADH was unchanged during exercise in McA patients in contrast to healthy subjects, in whom NADH increases markedly at high exercise intensities. Despite low lactate levels, arterial plasma NH3 and muscle inosine 5'-monophosphate increased more steeply relative to work load in McA patients than in healthy subjects. The low postexercise levels of lactate, acetylcarnitine, and NADH in McA patients support the idea that exercise performance is limited by the availability of oxidative fuels. Increases in muscle inosine 5'-monophosphate and plasma NH3 indicate that lack of glycogen as an oxidative fuel is associated with adenine nucleotide breakdown and increased deamination of AMP. It is suggested that the early onset of fatigue in McA patients is caused by an insufficient rate of ADP phosphorylation, resulting in transient increases in ADP.
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PMID:Impaired oxidative metabolism increases adenine nucleotide breakdown in McArdle's disease. 226 40

The origin of fatigue in McArdle's disease is still a matter of debate. Both a reduction of muscle membrane excitability and failure of excitation-contraction (E-C) coupling have been suggested as causes. We performed intermittent isometric biceps brachii contractions (80% maximal voluntary contraction, rate 30/min) under local ischaemia in 5 McArdle's disease patients and 26 healthy controls. Our results show that in McArdle's disease the exerted force is less, the surface EMG (SEMG) amplitude steadily increases, and that the power density spectrum (PDS) shifts to lower frequencies, the latter without significant differences when compared with normals. The most important finding is that muscle membrane excitability remains unimpaired during ischaemic exercise, establishing a dominant role for intramuscular lactic acid formation in the reduction of muscle fibre conduction velocity seen in normal subjects. As is indicated by the shift of the PDS towards lower frequencies, as well as by the increase in SEMG amplitude, it can be concluded that during ischaemic exercise in patients with myophosphorylase deficiency, fatigue occurs without alterations in muscle membrane excitability and is due to a failure of E-C coupling.
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PMID:Muscle fatigue in McArdle's disease. Muscle fibre conduction velocity and surface EMG frequency spectrum during ischaemic exercise. 227 44

1. The relationship between intracellular metabolites and the generation of force during fatigue has been examined in the first dorsal interosseous muscle of the hand. With the arm made ischaemic, the muscle was fatigued by three bouts of maximal voluntary contraction, leaving approximately three minutes ischaemic rest between contractions. During one series of experiments intracellular phosphorus metabolites were measured by nuclear magnetic resonance during the intervals between the fatiguing contractions: in the second series contractile properties were tested with brief electrical stimulation during the rest intervals. 2. The relationships between loss of force and change in metabolite concentrations obtained with four normal subjects were compared with those from one subject with myophosphorylase deficiency (MPD) who could not utilize muscle glycogen and therefore produced no hydrogen ion from glycolysis during exercise. 3. For both the MPD and normal subjects the relationship between relative force loss and inorganic phosphate (Pi) concentration was curvilinear, force changing little in the early stages of the contraction when the intracellular Pi was accumulating rapidly but falling faster when the Pi was above 25 mM and increasing relatively slowly. 4. In the normal subjects intracellular pH fell from a mean of 7.03 +/- 0.01 (mean +/- S.E. of mean, n = 19) in the fresh muscle to 6.51 +/- 0.02 at the end of the fatiguing exercise; force, as a percentage of the initial value, fell in proportion to the increase in H+ concentration. In the MPD subject pH did not change and force loss was therefore independent of H+ accumulation. In the normal subjects the force of the fatiguing muscle showed an approximately linear relationship with the concentration of the monobasic form of inorganic phosphate. However, the MPD subject showed a quite different relationship, with force loss being much greater for a given concentration of monobasic phosphate. This result indicates that monobasic phosphate is not a unique determinant of force loss in fatigued muscle. 5. During the first 60 s of recovery in the normal subjects, pH remained low while force recovered, indicating a mechanism of force loss that was independent of H+ accumulation. However, the recovery of force was not complete, so that for comparable phosphocreatine contents the recovering, more acid, muscle generated less force than the muscle that was being fatigued. It was estimated that H(+)-dependent and independent mechanisms contributed roughly equally to the observed force loss. The relationship between force and the concentration of monobasic phosphate differed in fatiguing and recovering muscle.
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PMID:Changes in force and intracellular metabolites during fatigue of human skeletal muscle. 262 21

1. The relationship between slowing of relaxation and changes of intracellular pH and phosphorous metabolites has been examined in human skeletal muscle during the development of fatigue and subsequent recovery. Results obtained with normal subjects have been compared with those from a subject with myophosphorylase deficiency (MPD) who produced no H+ from glycolysis during exercise and therefore afforded the opportunity of assessing the role of H+ in the slowing of relaxation. 2. Subjects fatigued the first dorsal interosseous muscle in a stepwise fashion under ischaemic conditions, with intervals between the fatiguing contractions during which the relaxation rate was measured from brief tetanic contractions and the muscle phosphorous metabolites and pH were measured by nuclear magnetic resonance spectroscopy. 3. After 21 s maximal voluntary contraction under ischaemic conditions, relaxation in the MPD subject slowed to approximately 50% of the rate in the fresh muscle at a time when the intramuscular pH had not changed. This demonstrates that there is a mechanism causing slowing of relaxation that is independent of H+ accumulation. 4. The normal subjects showed a slow recovery of relaxation compared to the MPD subject when the circulation was restored. The main difference in the intracellular metabolite concentrations between MPD and normal subjects at this time was that, for the latter, the pH remained low (around 6.5) for at least 60 s after the circulation was restored. The results suggest that the slow recovery is a consequence of continuing acidosis, i.e. the existence of a pH-dependent mechanism of slowing. 5. The existence of a pH-dependent mechanism was further indicated by the fact that for the normal subjects, for a similar intracellular concentration of phosphocreatine, relaxation of the recovering muscle was approximately half that of the fatiguing muscle. This was at a time when the pH of the recovering muscle was 0.3-0.4 units less than in the partially fatigued muscle. 6. The results show that in normal muscle there are at least two processes that lead to slow relaxation in fatigued muscle: one due to H+ accumulation, the other being independent of H+.
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PMID:The metabolic causes of slow relaxation in fatigued human skeletal muscle. 262 22

Exertional muscle pain and fatigue are common complaints; some patients with these symptoms have a metabolic myopathy. We have performed graded exercise testing with analysis of expired ventilation on 13 individuals with various kinds of metabolic myopathies. Their results differed from normal and reflected the underlying biochemical abnormality. Patients with disorders of the mitochondrial electron transport chain demonstrated marked limitations in aerobic metabolism and a greatly reduced maximum oxygen consumption. During intense exertion, normal individuals increase carbon dioxide generation due to buffering of lactic acid. This did not occur in patients with McArdle disease, in whom the respiratory exchange ratio (carbon dioxide production/oxygen consumption) did not rise above 1.0 at maximum exercise. These results indicated a deficit in anaerobic metabolism. Pyruvate dehydrogenase complex allows pyruvate produced from carbohydrate metabolism to enter the citric acid cycle. Patients with this enzyme deficiency showed an initially normal pattern followed by an abrupt cessation in carbohydrate dependent aerobic metabolism at higher work loads. During high-intensity exercise, progressive anaerobic metabolism was not accompanied by additional oxygen consumption. Finally, results from a patient with carnitine palmitoyl transferase deficiency revealed an early dependence on carbohydrate metabolism. The ventilatory threshold occurred at a low percentage of maximal oxygen consumption, reflecting the limited availability of lipid substrates for aerobic metabolism. Detection of some muscle metabolic abnormalities can be made on small biopsy specimens. However, definitive diagnosis of the defect nearly always requires studies on fresh or frozen muscle tissue obtained by an open biopsy. The decision on how the tissue should be processed and which metabolic studies should be performed frequently needs to be made before the biopsy is obtained. Thus, a noninvasive method to initially characterize patients with potential metabolic disorders is useful. Exercise testing with expired gas analysis can indicate the presence of a metabolic myopathy and results can then be used to direct the appropriate biochemical evaluations.
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PMID:Metabolic myopathies: evaluation by graded exercise testing. 271 15


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