Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0015672 (fatigue)
 51,768 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

Contractile properties of the adductor pollicis muscle were examined in 9 normal volunteers and 7 patients with histochemically proven myophosphorylase deficiency (McArdle's disease). Fatiguing contractions were produced by supramaximal stimulation of the ulnar nerve, delivered over a range of frequencies, to allow further examination of the mechanisms responsible for the premature fatigue in patients. The excessive reductions in force, demonstrated in patients at all frequencies, were not associated at high frequencies (50 and 100 Hz) with excessive declines in excitation (measured as compound muscle action potential). These results demonstrate that, in patients, myofibrillar activation failure occurs over and above that due to excitation failure. Abnormal slowing of relaxation mechanisms was also confirmed. These findings appear consistent with the hypothesis of inhibition of various ATPases by metabolic products. The observed, clear differences between normal subjects and myophosphorylase-deficient patients constitute the basis of an objective screening procedure for this and other glycolytic disorders.
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PMID:Myofibrillar activation failure in McArdle's disease. 280 26

It has been postulated that the power spectral shift in the surface EMG during fatigue is due to accumulation of muscle lactate. This hypothesis has been directly tested by measuring such shift in 3 patients with myophosphorylase deficiency who performed sustained isometric contractions of the quadriceps muscle. It was found that the spectral shift in these patients was greater than that in normal subjects, rendering lactate as a cause of this phenomenon very unlikely. The mechanism of excessive fatiguability in myophosphorylase deficiency is thought to be due to failure of excitation of the muscle membrane; further support for this postulate is provided and it is contended that accumulation of extracellular potassium ions may explain the phenomena of spectral shift in normals and myophosphorylase deficient patients and the excessive fatiguability in the latter.
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PMID:Muscle fatigue in myophosphorylase deficiency: power spectral analysis of the electromyogram. 620 Feb 96

McArdle's disease is defined as a lack of functional muscle glycogen phosphorylase. Analysis of the myophosphorylase gene has demonstrated substantial heterogeneity in the mutations that cause the disease, but in almost all individuals, the molecular phenotype is the absence of the protein in skeletal muscle. Muscle glycogen phosphorylase is a major repository of vitamin B6 in the body, accounting for at least 80% of the total body pool. In McArdle's patients, this pool is therefore missing, introducing the possibility that vitamin B6 metabolism might be altered in these individuals. Preliminary data have shown that McArdle's patients show signs of a subclinical vitamin B6 deficiency, and that oral vitamin B6 supplementation can improve vitamin B6 status and enhance fatigue resistance in muscle.
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PMID:McArdle's disease: molecular genetics and metabolic consequences of the phenotype. 760 21

Myophosphorylase deficiency or McArdle's disease is rarely recognized in childhood. The onset is generally in adolescence or in adult age with exercise intolerance, muscle cramps and myoglobinuria. Two siblings of 6 and 2 years of age are described. The first patient showed early fatigue and both had elevated CK levels. Morphological and biochemical studies of muscle biopsies revealed a defect of myophosphorylase.
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PMID:[Muscle phosphorylase deficiency in childhood. A case report]. 780 67

Mc Ardle's disease is a genetic glycogenosis characterized by the accumulation of glycogen in skeletal muscle secondary to the deficiency of muscle glycogen phosphorylase. The clinical consequences are an exercise intolerance with rapid muscle fatigue and muscle pain combined with a myoglobinuria. We report the medical story of a 45 years old man who suffers from Mc Ardle disease for ten years. He holds his family's doctor because of an oliguria and a weight gain of 5 kg after one week of skiing and one afternoon of gardening. Moreover he complains of quadriceps muscle pains. His urine is orange-red. The supplementary examinations show a rhabdomyolysis and an acute renal failure. The patient benefits of a hemodialysis treatment with a progressive and complete recovery of his renal function after two weeks of treatment.
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PMID:[One rare case report of acute renal insufficiency in rhabdomyolysis]. 1252 38

McArdle's disease is a rare, inherited deficiency of myophosphorylase, an enzyme required for the utilization of glycogen. Patients with myophosphorylase deficiency classically present with exercise intolerance, leg pain and muscle fatigue. The case of a young woman with exertional dyspnea and leg cramps is described. Exercise testing confirmed the presence of exercise intolerance and demonstrated an accelerated heart rate response, despite the absence of an anaerobic threshold and a respiratory exchange ratio of less than 1.0. Subsequent ischemic forearm testing and muscle biopsy confirmed the diagnosis of myophosphorylase deficiency. Evaluation of lung mechanics with esophageal pressure measurements demonstrated the presence of respiratory muscle weakness and early fatiguability, suggesting that the patient's dyspnea might have been attributable to an increased respiratory effort. Dyspnea is not a classic symptom associated with myophosphorylase deficiency, although subclinical respiratory muscle impairment may be present. No previous studies have evaluated respiratory muscle function during exercise in patients with myophosphorylase deficiency.
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PMID:McArdle's disease presenting as unexplained dyspnea in a young woman. 1504 49

McArdle disease (glycogenosis type V) is a metabolic myopathy with symptoms of exercise intolerance caused by deficiency of the enzyme myophosphorylase. In these patients, the motor nerve conduction studies after a short period of maximal voluntary muscle contraction or repetitive stimulation reveals characteristic findings of the disease. A 37-year-old man presented symptoms of exercise intolerance, muscular fatigue and cramps in the beginning of the physical activity with "second wind" phenomenon. The motor nerve conduction studies after a voluntary contraction of 30 and 90 seconds presented decrease in the amplitude of the compound muscle action potential in median, ulnar and deep peroneal nerves; and decrement after 200 stimulation at the 40 Hz in deep peroneal nerve. The electromyography presented myopathic pattern and during the ischemic exercise electric silence was not proven. The characteristic of electrophysiological studies are discussed with emphasis at the importance of the motor nerve conduction studies in the patients with suspicion of metabolic myopathy.
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PMID:[Motor nerve conduction study in McArdle disease: case report]. 1625 75

Glycogen phosphorylase inhibition represents a promising strategy to suppress inappropriate hepatic glucose output, while muscle glycogen is a major source of fuel during contraction. Glycogen phosphorylase inhibitors (GPi) currently being investigated for the treatment of type 2 diabetes do not demonstrate hepatic versus muscle glycogen phosphorylase isoform selectivity and may therefore impair patient aerobic exercise capabilities. Skeletal muscle energy metabolism and function are not impaired by GPi during high-intensity contraction in rat skeletal muscle; however, it is unknown whether glycogen phosphorylase inhibitors would impair function during prolonged lower-intensity contraction. Utilizing a novel red cell-perfused rodent gastrocnemius-plantaris-soleus system, muscle was pretreated for 60 min with either 3 micromol/l free drug GPi (n=8) or vehicle control (n=7). During 60 min of aerobic contraction, GPi treatment resulted in approximately 35% greater fatigue. Muscle glycogen phosphorylase a form (P<0.01) and maximal activity (P<0.01) were reduced in the GPi group, and postcontraction glycogen (121.8 +/- 16.1 vs. 168.3 +/- 8.5 mmol/kg dry muscle, P<0.05) was greater. Furthermore, lower muscle lactate efflux and glucose uptake (P<0.01), yet higher muscle Vo(2), support the conclusion that carbohydrate utilization was impaired during contraction. Our data provide new confirmation that muscle glycogen plays an essential role during submaximal contraction. Given the critical role of exercise prescription in the treatment of type 2 diabetes, it will be important to monitor endurance capacity during the clinical evaluation of nonselective GPi. Alternatively, greater effort should be devoted toward the discovery of hepatic-selective GPi, hepatic-specific drug delivery strategies, and/or alternative strategies for controlling excess hepatic glucose production in type 2 diabetes.
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PMID:The experimental type 2 diabetes therapy glycogen phosphorylase inhibition can impair aerobic muscle function during prolonged contraction. 1673 53

The rosuvastatin inducing rhabdomyolysis in McArdle disease (MD) has not been reported to date. A 35-years-old man had exercise intolerance, muscular fatigue and cramps during physical activity since infancy. He presented severe rhabdomyolysis episode with seizure and coma after use of rosuvastatin. The investigation showed increased serum creatine-kinase levels and the forearm ischemic exercise did not increase venous lactate. The muscle biopsy showed subsarcolemmal and central accumulation of glycogen and absence of the myophosphorylase enzyme. The statin induced myopathy is discussed and the danger of its use in MD is emphasized.
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PMID:McArdle disease with rhabdomyolysis induced by rosuvastatin: case report. 1795 91


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