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)

1. Increased myoplasmic inorganic phosphate (P(i)) has been suggested to have an important role in skeletal muscle fatigue, especially in the early phase. In the present study we used intact fast-twitch muscle cells from mice completely deficient in creatine kinase (CK(-/-)) to test this suggestion. These CK(-/-) muscle cells provide a good model since they display a higher P(i) concentration in the unfatigued state and fatigue without significant increase of P(i). 2. Tetanic contractions (350 ms duration) were produced in intact single muscle fibres. The free myoplasmic [Ca(2+)] ([Ca(2+)](i)) was measured with the fluorescent indicator indo-1. The force-[Ca(2+)](i) relationship was constructed from tetani at different frequencies. 3. Compared with wild-type fibres, CK(-/-) fibres displayed lower force in 100 Hz tetani and at saturating [Ca(2+)](i) (i.e. 100 Hz stimulation during caffeine exposure), higher tetanic [Ca(2+)](i) during the first 100 ms of tetanic stimulation, reduced myofibrillar Ca(2+) sensitivity when measurements were performed 100-200 ms into tetani, and slowed force relaxation that was due to altered cross-bridge kinetics rather than delayed Ca(2+) removal from the myoplasm. 4. In wild-type fibres, a series of 10 tetani resulted in reduced tetanic force, slowed force relaxation, and increased amplitude of [Ca(2+)](i) tails after tetani. None of these changes were observed in CK(-/-) fibres. 5. Complementary experiments on isolated fast-twitch extensor digitorum longus muscles showed a reduction of tetanic force and relaxation speed in CK(-/-) muscles similar to those observed in single fibres. 6. In conclusion, increased P(i) concentration can explain changes observed in the early phase of skeletal muscle fatigue. Increased P(i) appears to be involved in both fatigue-induced changes of cross-bridge function and SR Ca(2+) handling.
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PMID:Role of myoplasmic phosphate in contractile function of skeletal muscle: studies on creatine kinase-deficient mice. 1138 99

1. Ca(2+)-phosphate (P(i)) precipitation in the sarcoplasmic reticulum (SR) may cause reduced SR Ca(2+) release in skeletal muscle fatigue. To study this, we inhibited the creatine kinase (CK) reaction with 2,4-dinitro-1-fluorobenzene (DNFB). The hypothesis was that with inhibition of CK, phosphocreatine would not break down to creatine and P(i). Therefore P(i) transport into the SR would be limited and Ca(2+)-P(i) precipitation would not occur. 2. Intact single fibres from a mouse foot muscle were fatigued by repeated short tetani under control conditions or after exposure to DNFB (10 microM). The free myoplasmic concentrations of Ca(2+) ([Ca(2+)](i)) and Mg(2+) ([Mg(2+)](i)) were measured with indo-1 and mag-indo-1, respectively. Changes in [Mg(2+)](i) were assumed to reflect alterations in myoplasmic ATP concentration. 3. During the first 10 fatiguing tetani, tetanic [Ca(2+)](i) increased both in control and after DNFB exposure. Thereafter tetanic [Ca(2+)](i) fell and the rate of fall was about fourfold lower after DNFB exposure compared with control. 4. Under control conditions, there was a good relationship between declining tetanic [Ca(2+)](i) and increasing [Mg(2+)](i) during the final part of fatiguing stimulation. This correlation was lost after DNFB exposure. 5. In conclusion, the present data fit with a model where Ca(2+)-P(i) precipitation inhibits SR Ca(2+) release in fatigue produced by repeated short tetani. Furthermore, the results suggest that the rate of P(i) transport into the SR critically depends on the myoplasmic Mg(2+)/ATP concentration.
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PMID:Inhibition of creatine kinase reduces the rate of fatigue-induced decrease in tetanic [Ca(2+)](i) in mouse skeletal muscle. 1141 Jun 23

Our objective was to determine the maximum tolerated doses of tirapazamine and cyclophosphamide given i.v. in combination. Eligible patients had advanced solid tumors refractory to conventional treatment. Tirapazamine (escalated from 80 to 390 mg/m(2)) was given i.v. over 2 h and followed by cyclophosphamide over 1 h. The cyclophosphamide dose was fixed at 1000 mg/m(2) until the tirapazamine dose of 390 mg/m(2) was reached. Once that dose of tirapazamine was reached, the cyclophosphamide dose was escalated to 1250 and 1500 mg/m(2). Twenty-eight patients were enrolled. The dose-limiting toxicity was granulocytopenia. One patient had transient deafness for 2 days. Four other patients had grade 1 ototoxicity. Grade 1 and 2 muscle cramps were observed at all dose levels. Other toxic effects observed included fatigue, nausea, vomiting, headache, diarrhea, drug fever, elevated transaminases and elevated creatine phosphokinase. Three patients had stable disease and the longest time to progression was 5 months. The combination of tirapazamine and cyclophosphamide is feasible, and the dose-limiting toxicity is granulocytopenia. The use of growth factors could possibly allow escalation of tirapazamine doses in future phase II trials. Without growth factor support, the recommended doses of tirapazamine and cyclophosphamide when administered in this schedule are 260 and 1000 mg/m(2), respectively.
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PMID:Phase I trial of i.v. administered tirapazamine plus cyclophosphamide. 1145 95

Intensive activity of muscles causes a decline in performance, known as fatigue, that is thought to be caused by the effects of metabolic changes on either the contractile machinery or the activation processes. The concentration of inorganic phosphate (P(i)) in the myoplasm ([P(i)](myo)) increases substantially during fatigue and affects both the myofibrillar proteins and the activation processes. It is known that a failure of sarcoplasmic reticulum (SR) Ca(2+) release contributes to fatigue and in this review we consider how raised [P(i)](myo) contributes to this process. Initial evidence came from the observation that increasing [P(i)](myo) causes reduced SR Ca(2+) release in both skinned and intact fibres. In fatigued muscles the store of releasable Ca(2+) in the SR declines mirroring the decline in SR Ca(2+) release. In muscle fibres with inoperative creatine kinase the rise of [P(i)](myo) is absent during fatigue and the failure of SR Ca(2+) release is delayed. These results can all be explained if inorganic phosphate can move from the myoplasm into the SR during fatigue and cause precipitation of CaP(i) within the SR. The relevance of this mechanism in different types of fatigue in humans is considered.
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PMID:Role of phosphate and calcium stores in muscle fatigue. 1169 62

The ability to perform well in activities that require muscular and cardiorespiratory endurance is a trait influenced, in a considerable part, by the genetic make-up of individuals. Early studies of performance and recent scans of the human genome have pointed at various candidate genes responsible for the heterogeneity of these phenotypes within the population. Among these are the genes for the various creatine kinase (CK) isoenzyme subunits. CK and phosphocreatine (PCr) form an important metabolic system for temporal and spatial energy buffering in cells with large variations in energy demand. The different CK isoenzyme subunits (CK-M and CK-B) are differentially expressed in the tissues of the body. Although CK-M is the predominant form in both skeletal and cardiac muscle, CK-B is expressed to a greater extent in heart than in skeletal muscle. Studies in humans and mice have shown that the expression of CK-B messenger RNA (mRNA) and the abundance and activity of the CK-MB dimer increase in response to cardiorespiratory endurance training. Increases in muscle tissue CK-B content can be energetically favourable because of its lower Michaelis constant (Km) for ADP. The activity of the mitochondrial isoform of CK (Scmit-CK) has also been significantly and positively correlated to oxidative capacity and to CK-MB activity in muscle. In mice where the CK-M gene has been knocked out, significant increases in fatigue resistance together with cellular adaptations increasing aerobic capacity have been observed. These observations have led to the notion that this enzyme may be responsible for fatigue under normal circumstances, most likely because of the local cell compartment increase in inorganic phosphate concentration. Studies where the Scmit-CK gene was knocked out have helped demonstrate that this isoenzyme is very important for the stimulation of aerobic respiration. Human studies of CK-M gene sequence variation have shown a significant association between a polymorphism, distinguished by the NcoI restriction enzyme, and an increase in cardiorespiratory endurance as indexed by maximal oxygen uptake following 20 weeks of training. In conclusion, there is now evidence at the tissue, cell and molecular level indicating that the CK-PCr system plays an important role in determining the phenotypes of muscular and cardiorespiratory endurance. It is envisioned that newer technologies will help determine how the genetic variability of these genes (and many others) impact on performance and health-related phenotypes.
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PMID:Role of creatine kinase isoenzymes on muscular and cardiorespiratory endurance: genetic and molecular evidence. 1170 1

This article describes three cases of undiagnosed hypothyroidism in a developed stage which manifest themselves with myopathic syndrome (myalgia, muscular fatigue, and higher serum levels of creatine kinase, aminotranferases, and lactate dehydrogenase) without the "classic" symptoms of hypothyroidism. In addition, two of the three patients were receiving hypolipidemic drugs for secondary hyperlipoproteinemia, which could have affected the development of the myopathy. Emphasis is placed on the description of atypical symptoms of hypothyroidism and the necessity of endocrinological examination in each case of myopathy with indefinite etiology.
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PMID:[Myopathy syndrome in undiagnosed hypothyroidism]. 1171 70

A 43-year-old woman complained of colicky abdominal pain, followed by numbness, myalgias, and muscle weakness in the four limbs after eating a grouper (Epinepheius spp.). She presented to our hospital 36 hours later with increased myalgias, muscle weakness, and malaise. On examination, the muscle power and sensation in her four limbs appeared to be normal. She was given an intravenous infusion of mannitol 20% (200 ml over 1 hour) and an intramuscular injection of diclofenac (75 mg). Her myalgias then improved and she was discharged. She presented to our hospital again 1 week later with poor appetite, malaise, numbness of the four limbs, and increased muscle weakness. On examination, the muscle weakness was more marked in the lower limbs (4+/5) than in the upper limbs (5-/5) and proximally than distally. She also had some difficulty in getting up from a squatting position. She was given another intravenous infusion of mannitol 20% (200 ml over 1 hour), following which there was subjectively slight improvement in her muscle weakness. Herplasma creatine phosphokinase level was normal. Electromyography performed 4 weeks later revealed no abnormalities. When she was reviewed 45 days after the consumption of the grouper, her muscle weakness and malaise had improved considerably. She could then stand up from a squatting position. However, mild impairment of finger grip was still present. Chronicity of neurological features in other reported cases (e.g., chronic fatigue, relapse of symptoms after exposure to ciguateric fish or alcohol, and peripheral neuropathy) may also indicate a lengthy persistence of ciguatoxins in the body.
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PMID:Chronicity of neurological features in ciguatera fish poisoning. 1172 94

A 50-year-old man had been well until three months earlier, when he felt general fatigue, and cutaneous rash with itching. Thereafter a general muscular weakness developed and the patient could not walk for a month. Four weeks before referral to our hospital, he had high fever and could not role over in the bed. On admission, the patient was able to walk. He had no skin rash. Neurologically, he showed mild weakness in proximal muscles. Hematologic examination showed mild eosinophilia and serum creatine kinase was mildly elevated. Needle electromyogram revealed a diffuse myogenic pattern in extremities. Eosinophilic myositis was diagnosed by a biopsy of the left calf muscle showing mild infiltration of eosinophilis which was identified using antibodies against eosinophilic granule protein.
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PMID:[A case of eosinophilic myositis proven by immunohistochemistry using antibodies against eosinophilic granule protein]. 1180 47

To evaluate the frequency of clinical manifestations and to study the etiological aspects of hypothyroidism in hypothyroid patients in Cotonou, we carried out a retrospective analysis of the medical reports on hypothyroid patients followed in our clinical practice. A total of 33 patients was thus studied, comprising 8 men (24%) and 25 women (76%) with mean age of 45,8 years for men and 40,4 years for women. The more frequent clinical manifestations observed were: face edema (45%), weight gain (45%), paresthesia (42%), fatigue (39%), lethargy (30%) and bradycardia (24%). Constipation (12%), sensation of cold (9%), depilation (6%) and dry skin (6%) were less frequently observed. Myalgia, hoarseness and menstrual irregularities were present in 15% of the cases respectively. Regarding the etiology, 82% of the cases were primary hypothyroidism and only 18% were of central origin. Thyroidectomy was the leading cause in our hypothyroid patients, representing 70% of all cases and 85% of primary hypothyroidism. Radioiodine treatment and autoimmune thyroiditis were equally found in 6% of the cases. Central hypothyroidism was related to a pituitary adenoma in four cases (12%) and to Sheehan syndrome in two cases (6%). As it can be expected, hypercholesterolemia was present in 82% of the patients but creatine phosphokinase elevation was more frequent (94% of the patients). Compared to the data reported in the literature, the frequency of the symptoms and signs of hypothyroidism seems to be underevaluated in our study and the frequency of autoimmune thyroiditis as a cause of hypothyroidism is low.
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PMID:[Hypothyroidism: clinical and etiological aspects in Cotonou (Republic of Benin)]. 1186 Dec 1

Force declines when muscles are used repeatedly and intensively and a variety of intracellular mechanisms appear to contribute to this muscle fatigue. Intracellular calcium release declines during fatigue and has been shown to contribute to the reduction in force. Three new approaches have helped to define the role of calcium stores to this decline in calcium release. Skinned fibre experiments show that when intracellular phosphate is increased the amount of Ca2+ released from the sarcoplasmic reticulum (SR) declines. Intact fibre experiments show that the size of the calcium store declines during fatigue and recovers on rest. Intact muscles which lack the enzyme creatine kinase, do not exhibit the usual rise of phosphate during fatigue and, under these conditions, the decline of Ca2+ release is absent or delayed. These results can be explained by the "calcium phosphate precipitation" hypothesis. This proposes that if phosphate in the myoplasm rises, it enters the SR and binds to Ca2+ as Ca2+ phosphate. The resultant reduction in free Ca2+ within the SR contributes to the reduced Ca2+ release during fatigue.
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PMID:Muscle fatigue: the role of intracellular calcium stores. 1188 Jun 93


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