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

The use of MRS has become more widespread as cost and availability have improved. It has been demonstrated that MRS of human skeletal muscle can play a significant role in (1) understanding healthy muscle metabolism and the mechanisms of muscle fatigue, (2) understanding the effects of disease on muscle metabolism and function, (3) monitoring the efficacy of therapeutic intervention, and (4) the confirmation of disease diagnoses. The results of the 31P MRS studies of disease are summarized in the Table 1. A few conditions (McArdle's, PFK deficiency) are associated with failure to develop acidosis during exercise. This response appears to be relatively specific to these metabolic myopathies. For most of the conditions reviewed here, however, the metabolic findings of reduced PCr/Pi and greater acidosis during exercise with impaired recovery of PCr/Pi and pH are very similar. The nonspecificity of the MRS results suggests the possibility that a common mechanism may be at work in all of these diseases. A major question to arise from clinical studies using MRS concerns the extent to which deconditioning may have played a role in some of these findings. This is because conditions associated with muscle weakness, rapid fatiguability, and muscle pain during or following vigorous physical activity may also be those that lead to deconditioning. In virtually all studies reviewed here, healthy, active subjects were used as controls. There are no examples in which controls were appropriately matched to the subjects for their level of conditioning. Conditioning could be assessed by questionnaire, activity logs, activity monitoring devices, or measurements of conditioning effects such as maximal oxygen consumption. The role of deconditioning in the decreased quality of life of persons with chronic diseases has not been fully explored. Future studies of chronic disease using MRS should combine MRS with other techniques to further probe the mechanisms of muscle metabolism under various conditions, and the extent to which these mechanisms are sensitive to the level of physical conditioning.
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PMID:Magnetic resonance spectroscopy studies of human muscle. 814 Feb 29

Muscle may suffer from a number of diseases or disorders, some being fatal to humans and animals. Their management or treatment depends on correct diagnosis. Although no single method may be used to identify all diseases, recognition depends on the following diagnostic procedures: (1) history and clinical examination, (2) blood biochemistry, (3) electromyography, (4) muscle biopsy, (5) nuclear magnetic resonance, (6) measurement of muscle cross-sectional area, (7) tests of muscle function, (8) provocation tests, and (9) studies on protein turnover. One or all of these procedures may prove helpful in diagnosis, but even then identification of the disorder may not be possible. Nevertheless, each of these procedures can provide useful information. Among the most common diseases in muscle are the muscular dystrophies, in which the newly identified muscle protein dystrophin is either absent or present at less than normal amounts in both Duchenne and Becker's muscular dystrophy. Although the identification of dystrophin represents a major breakthrough, treatment has not progressed to the experimental stage. Other major diseases of muscle include the inflammatory myopathies and neuropathies. Atrophy and hypertrophy of muscle and the relationship of aging, exercise, and fatigue all add to our understanding of the behavior of normal and abnormal muscle. Some other interesting related diseases and disorders of muscle include myasthenia gravis, muscular dysgenesis, and myclonus. Disorders of energy metabolism include those caused by abnormal glycolysis (Von Gierke's, Pompe's, Cori-Forbes, Andersen's, McArdle's, Hers', and Tauri's diseases) and by the acquired diseases of glycolysis (disorders of mitochondrial oxidation). Still other diseases associated with abnormal energy metabolism include lipid-related disorders (carnitine and carnitine palmitoyl-transferase deficiencies) and myotonic syndromes (myotonia congenita, paramyotonia congenita, hypokalemic and hyperkalemic periodic paralysis, and malignant hyperexia). Diseases of the connective tissues discussed include those of nutritional origin (scurvy, lathyrism, starvation, and protein deficiency), the genetic diseases (dermatosparaxis, Ehlers-Danlos syndrome, osteogenesis imperfecta, Marfan syndrome, homocystinuria, alcaptonuria, epidermolysis bullosa, rheumatoid arthritis in humans, polyarthritis in swine, Aleutian disease of mink, and the several types of systemic lupus erythematosus) and the acquired diseases of connective tissues (abnormal calcification, systemic sclerosis, interstitial lung disease, hepatic fibrosis, and carcinomas of the connective tissues). Several of the diseases of connective tissues may prove to be useful models for determining the relationship of collagen to meat tenderness and its other physical properties. Several other promising models for studying the nutrition-related disorders and the quality-related characteristics of meat are also reviewed.
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PMID:Diseases and disorders of muscle. 839 47

To determine whether seven days oral D-ribose would improve exercise tolerance in a group of 5 patients with McArdle's disease, we performed a double blind placebo controlled crossover trial. Subjects performed weekly treadmill exercise tests with expired gas analysis until their times were reproducible. They then received 60 g D-ribose daily or placebo for seven days. Exercise testing was repeated on completion of this period. A seven day washout period then followed. Subjects then performed a new baseline exercise test prior to starting the other solution. Again after seven days the exercise test was repeated. There was no significant difference between pre-treatment exercise tests for peak oxygen consumption or level of leg fatigue. Patients did not like taking the ribose and D-Ribose does not appear to be of benefit to patients with McArdle's disease.
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PMID:A double blind, placebo controlled, crossover trial of D-ribose in McArdle's disease. 881 68

We evaluated the hypothesis that impaired sarcolemmal function associated with exaggerated potassium release, impaired potassium uptake, or both may contribute to exertional fatigue and abnormal circulatory responses to exercise in McArdle disease (MD). The cellular mechanism of exertional fatigue and muscle injury in MD is unknown but likely involves impaired function of the ATPases that couple ATP hydrolysis to cellular work, including the muscle sodium potassium pump (Na+K+-ATPase). However, the concentration of muscle Na+K+ pumps in MD is not known, and no studies have related exercise increases in blood potassium concentrations to muscle Na+K+ pump levels. We measured muscle Na+K+ pumps (3H-ouabain binding) and plasma K+ in response to 20 minutes of cycle exercise in six patients with MD and in six sex-, age-, and weight-matched sedentary individuals. MD patients had lower levels of 3H-ouabain binding (231 +/- 18 pmol/g w.w., mean +/- SD, range, 210 to 251) than control subjects (317 +/- 37, range, 266 to 371, p < 0.0004), higher peak increases in plasma potassium in response to 45 +/- 7 W cycle exercise (MD, 1.00 +/- 0.15 mmol/L; control subjects, 0.48 +/- 0.09; p < 0.0001), and mean exercise heart rate responses to exercise that were 45 +/- 12 bpm greater than control subjects. Our results indicate that Na+K+ pump levels are low in MD patients compared with healthy subjects and identify a limitation of potassium reuptake that could result in sarcolemmal failure during peak rates of membrane activation and may promote exaggerated potassium-activated circulatory responses to submaximal exercise. The mechanism of the low Na+K+ pump concentrations in MD is unknown but may relate to deconditioning or to disruption of a close functional relationship between membrane ion transport and glycolysis.
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PMID:Reduced levels of skeletal muscle Na+K+ -ATPase in McArdle disease. 944 49

Creatine is a dietary supplement purported to improve exercise performance and increase fat-free mass. Recent research on creatine has demonstrated positive therapeutic results in various clinical applications. The purpose of this review is to focus on the clinical pharmacology and therapeutic application of creatine supplementation. Creatine is a naturally occurring compound obtained in humans from endogenous production and consumption through the diet. When supplemented with exogenous creatine, intramuscular and cerebral stores of creatine and its phosphorylated form, phosphocreatine, become elevated. The increase of these stores can offer therapeutic benefits by preventing ATP depletion, stimulating protein synthesis or reducing protein degradation, and stabilizing biological membranes. Evidence from the exercise literature has shown athletes benefit from supplementation by increasing muscular force and power, reducing fatigue in repeated bout activities, and increasing muscle mass. These benefits have been applied to disease models of Huntington's, Parkinson's, Duchenne muscular dystrophy, and applied clinically in patients with gyrate atrophy, various neuromuscular disorders, McArdle's disease, and congestive heart failure. This review covers the basics of creatine synthesis and transport, proposed mechanisms of action, pharmacokinetics of exogenous creatine administration, creatine use in disease models, side effects associated with use, and issues on product quality.
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PMID:Clinical pharmacology of the dietary supplement creatine monohydrate. 1135 82

During static exercise, metabolites accumulate in the muscle interstitium where they stimulate chemosensitive afferent nerves that reflexly increase efferent muscle sympathetic nerve activity (MSNA) and blood pressure. In experimental animals, lactic acid potently stimulates the muscle metaboreflex, but its role in humans is more controversial. To determine if lactic acid is a critical mediator of metaboreflex activation in humans, we performed microelectrode recordings of MSNA in eight patients with myophosphorylase deficiency (McArdle's disease) who cannot metabolize intramuscular glycogen and do not generate lactic acid in exercising muscles. Each patient was matched with three healthy control subjects to maximize statistical power. In controls, 2 min of static handgrip performed at 33 % or 45 % of maximal voluntary contraction (MVC) produced intensity-dependent increases in MSNA (171 +/- 22 % and 379 +/- 95 %, respectively). In the patients, MSNA responses to static handgrip were markedly attenuated (33 +/- 14 % at 33 % MVC; 32 +/- 19 % at 45 % MVC; P < 0.05 vs. controls). Likewise, when static handgrip (30 % MVC) was performed to fatigue, MSNA increased by 366 +/- 73 % in controls but only by 51 +/- 14 % in patients (P < 0.05). Pressor responses to static handgrip were also attenuated in patients compared to controls, whereas heart rate responses were identical. In contrast to exercise, the MSNA responses to other reflex stimuli (the cold pressor test or Valsalva's manoeuvre) were similar in patients and controls. Together these data indicate that appropriate activation of glycogenolytic pathways is obligatory for normal metaboreflex-mediated sympathoexcitation during static exercise in humans.
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PMID:Reflex sympathetic activation during static exercise is severely impaired in patients with myophosphorylase deficiency. 1264 3

Energy metabolism and electrical muscle activity were studied in the calf muscles of 19 patients with proven McArdle's disease and in 25 healthy subjects. Phosphorus magnetic resonance spectroscopy and surface electromyography (S-EMG) were performed during two isometric muscle contractions of 3 min at 30% maximum voluntary contraction, one performed during normal perfusion and the other during applied ischemia. After about 1 min of ischemic muscle contraction in diseased muscle a significant acceleration in phosphocreatine breakdown was observed, along with a significant decrease in adenosine triphosphate. During both contractions the absence of glycolysis was shown by a significant alkalinization. Furthermore, in patients we observed a greater increase in the S-EMG amplitude than in control subjects. We conclude that early on during moderate exercise, a small number of muscle fibers reach metabolic depletion, indicated by a reduction in the adenine nucleotide pool. An increasing number of motor units, which are still in a high-energy state, are continuously recruited to compensate for muscle fatigue. This functional compartmentation may contribute to the pathophysiology of exercise intolerance in McArdle's disease.
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PMID:Breakdown of adenine nucleotide pool in fatiguing skeletal muscle in McArdle's disease: a noninvasive 31P-MRS and EMG study. 1276 85

In skeletal muscle, excitation may cause loss of K+, increased extracellular K+ ([K+]o), intracellular Na+ ([Na+]i), and depolarization. Since these events interfere with excitability, the processes of excitation can be self-limiting. During work, therefore, the impending loss of excitability has to be counterbalanced by prompt restoration of Na+-K+ gradients. Since this is the major function of the Na+-K+ pumps, it is crucial that their activity and capacity are adequate. This is achieved in two ways: 1) by acute activation of the Na+-K+ pumps and 2) by long-term regulation of Na+-K+ pump content or capacity. 1) Depending on frequency of stimulation, excitation may activate up to all of the Na+-K+ pumps available within 10 s, causing up to 22-fold increase in Na+ efflux. Activation of the Na+-K+ pumps by hormones is slower and less pronounced. When muscles are inhibited by high [K+]o or low [Na+]o, acute hormone- or excitation-induced activation of the Na+-K+ pumps can restore excitability and contractile force in 10-20 min. Conversely, inhibition of the Na+-K+ pumps by ouabain leads to progressive loss of contractility and endurance. 2) Na+-K+ pump content is upregulated by training, thyroid hormones, insulin, glucocorticoids, and K+ overload. Downregulation is seen during immobilization, K+ deficiency, hypoxia, heart failure, hypothyroidism, starvation, diabetes, alcoholism, myotonic dystrophy, and McArdle disease. Reduced Na+-K+ pump content leads to loss of contractility and endurance, possibly contributing to the fatigue associated with several of these conditions. Increasing excitation-induced Na+ influx by augmenting the open-time or the content of Na+ channels reduces contractile endurance. Excitability and contractility depend on the ratio between passive Na+-K+ leaks and Na+-K+ pump activity, the passive leaks often playing a dominant role. The Na+-K+ pump is a central target for regulation of Na+-K+ distribution and excitability, essential for second-to-second ongoing maintenance of excitability during work.
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PMID:Na+-K+ pump regulation and skeletal muscle contractility. 1450 6

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

A 35-year-old patient had persistent, refractory symptomatic pulmonary sarcoidosis, complicated by a rare congenital muscular disease: McArdle's disease (a glycogen storage disease caused by myophosphorylase deficiency). As the desaturations during mild exercise caused by the sarcoidosis aggravated the negative consequences of his muscle disease and he failed to respond adequately to corticosteroids and methotrexateimmunosuppressive agents, the patient was successfully treated experimentally with infliximab, a monoclonal antibody and specific tumour necrosis factor alpha (TNF-alpha) inhibitor. The results were favourable: after 17, 21 and 36 months there was an improvement in various lung function parameters, his fatigue was reduced and the patient had been able to resume his work as a taxi driver. TNF-alpha appears to be an important mediator of clinical disease in sarcoidosis and infliximab could be a promising therapy for patients with refractory sarcoidosis.
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PMID:[Successful treatment with infliximab of a patient with refractory sarcoidosis]. 1562 11


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