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)

The aim was to investigate metabolic response in muscle during submaximal treadmill exercise to fatigue, with a special emphasis on adenine nucleotide degradation products such as inosine monophosphate (IMP) in muscle and hypoxanthine, xanthine and uric acid in plasma. Five Standardbred trotters performed treadmill exercise on 2 occasions, once at 7 m/s and once at 10 m/s. Venous blood samples were taken at rest, during exercise and at the end of exercise. Muscle biopsies were taken before and after exercise and muscle temperature was measured before and after exercise. Running time differed among horses and was 48-58 min at 7 m/s and 10-15.5 min at 10 m/s. Both lactate and uric acid concentrations in plasma showed a gradual increase during exercise at both 7 and 10 m/s. At the end of exercise, values for uric acid were higher and values for lactate lower at 7 m/s compared with at 10 m/s. No marked changes were seen in plasma concentrations of hypoxanthine or xanthine with exercise. Muscle glycogen decreased after exercise at both 7 and 10 m/s with a marked depletion seen in some fibres. Muscle lactate concentrations increased after exercise at both 7 m/s and at 10 m/s. No significant changes were seen in adenosine triphosphate (ATP), ADP and AMP concentrations, whereas IMP concentrations increased after exercise at both 7 m/s and at 10 m/s. The results of this study indicate that AMP deamination occurs with submaximal exercise and that development of fatigue may be related to adenine nucleotide degradation in muscle.
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PMID:Muscle adenine nucleotide degradation during submaximal treadmill exercise to fatigue. 1065 72

The aim was to study metabolic response and locomotion pattern in Standardbred trotters during incremental treadmill exercise performed by increasing speed by 1 m/s in 1 min steps (start 7 m/s) until the onset of fatigue. The test protocol included determination of oxygen uptake, heart rate (HR), stride length (SL) and stride frequency (SF). Venous blood samples were collected at rest, at the end of each exercise step and after 30 min of recovery. Muscle biopsies were taken at rest and post exercise and muscle temperature was measured after exercise. As horses fatigued at different speed steps (9-11 m/s), variation was seen in running time (180-300 s), oxygen uptake (109-170 ml/kg bwt min), HR (200-225 beats/min), SL (4.4-5.7 m) and SF (116-130 strides/min) at the last speed step. Increased mean plasma lactate concentration (20.5 mmol/l) was seen at onset of fatigue and increased mean uric acid concentration after 30 min of recovery (112.8 mumol/l). After exercise, a decrease was seen in muscle ATP (7.1 mmol/kg d.w.), creatine phosphate (43.9 mmol/kg d.w.) and glycogen (160 mmol/kg d.w.), and an increase was seen in ADP (0.3 mmol/kg d.w.), AMP (0.18 mmol/kg d.w.), IMP (5.8 mmol/kg d.w.) and lactate (100.8 mmol/kg d.w.). At onset of fatigue, muscle temperature varied from 39.9-41.4 degrees C. Running time correlated with SL (r = 0.86), with an increase in IMP (r = 0.79) and AMP (r = 0.70) post exercise and with plasma uric acid concentration (r = 0.74) at 30 min of recovery. SF correlated negatively with the increase in ADP after exercise (r = 0.85). The results of this study indicate that running time during incremental treadmill exercise until the onset of fatigue is related to locomotion pattern and to a marked degree of anaerobic metabolism, especially adenine nucleotide degradation.
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PMID:Incremental treadmill exercise until onset of fatigue and its relationship to metabolic response and locomotion pattern. 1065 79

Creatine kinase (CK) is a key enzyme for maintaining a constant ATP/ADP ratio during rapid energy turnover. To investigate the role of CK in skeletal muscle fatigue, we used isolated whole muscles and intact single fibers from CK-deficient mice (CK(-/-)). With high-intensity electrical stimulation, single fibers from CK(-/-) mice displayed a transient decrease in both tetanic free myoplasmic [Ca(2+)] ([Ca(2+)](i), measured with the fluorescent dye indo-1) and force that was not observed in wild-type fibers. With less intense, repeated tetanic stimulation single fibers and EDL muscles, both of which are fast-twitch, fatigued more slowly in CK(-/-) than in wild-type mice; on the other hand, the slow-twitch soleus muscle fatigued more rapidly in CK(-/-) mice. In single wild-type fibers, tetanic force decreased and [Ca(2+)](i) increased during the first 10 fatiguing tetani, but this was not observed in CK(-/-) fibers. Fatigue was not accompanied by phosphocreatine breakdown and accumulation of inorganic phosphate in CK(-/-) muscles. In conclusion, CK is important for avoiding fatigue at the onset of high-intensity stimulation. However, during more prolonged stimulation, CK may contribute to the fatigue process by increasing the myoplasmic concentration of inorganic phosphate.
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PMID:Is creatine kinase responsible for fatigue? Studies of isolated skeletal muscle deficient in creatine kinase. 1078 53

Contraction-induced respiratory muscle fatigue and sepsis-related reductions in respiratory muscle force-generating capacity are mediated, at least in part, by reactive oxygen species (ROS). The subcellular sources and mechanisms of generation of ROS in these conditions are incompletely understood. We postulated that the physiological changes associated with muscle contraction (i.e., increases in calcium and ADP concentration) stimulate mitochondrial generation of ROS by a phospholipase A(2) (PLA(2))-modulated process and that sepsis enhances muscle generation of ROS by upregulating PLA(2) activity. To test these hypotheses, we examined H(2)O(2) generation by diaphragm mitochondria isolated from saline-treated control and endotoxin-treated septic animals in the presence and absence of calcium and ADP; we also assessed the effect of PLA(2) inhibitors on H(2)O(2) formation. We found that 1) calcium and ADP stimulated H(2)O(2) formation by diaphragm mitochondria from both control and septic animals; 2) mitochondria from septic animals demonstrated substantially higher H(2)O(2) formation than mitochondria from control animals under basal, calcium-stimulated, and ADP-stimulated conditions; and 3) inhibitors of 14-kDa PLA(2) blocked the enhanced H(2)O(2) generation in all conditions. We also found that administration of arachidonic acid (the principal metabolic product of PLA(2) activation) increased mitochondrial H(2)O(2) formation by interacting with complex I of the electron transport chain. These data suggest that diaphragm mitochondrial ROS formation during contraction and sepsis may be critically dependent on PLA(2) activation.
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PMID:PLA(2) dependence of diaphragm mitochondrial formation of reactive oxygen species. 1090 37

The aim of the present study was to investigate the effect of creatine (Cr) supplementation on muscle metabolic response in connection with a maximal treadmill exercise test, known to cause a marked anaerobic metabolic response and adenine nucleotide degradation. First, 6 Standardbred trotters performed a standardised maximal exercise test until fatigue (baseline test). The test used was an inclined incremental treadmill test in which the speed was increased by 1 m/s, starting at 7 m/s, every 60 s until the horse could no longer keep pace with the treadmill. After this baseline test, the horses were separated into 2 equal groups. One half received a dose of 25 g creatine monohydrate twice daily, and the other group were given the same dose of lactose (placebo). The supplementation period was 6.5 days, after which the maximal treadmill exercise test was performed again. A washout period of 14 days was allowed before treatments were switched between groups and a new supplementation period started. After this second supplementation period a new maximal exercise test was performed. After supplementation with creatine or placebo, horses were stopped after performing the same number of speed steps and duration of exercise as they had in the baseline test. Blood samples for analysis of plasma lactate, creatine (Cr), creatinine, hypoxanthine, xanthine and uric acid concentrations were collected at rest, during each speed step and during recovery. The total blood volume (TBV) was also determined. Muscle biopsies for analysis of muscle metabolites (adenosine triphosphate [ATP], adenosine diphosphate [ADP], adenosine monophosphate [AMP], inosine monophosphate [IMP], creatine phosphate [CP], lactate [La] and glycogen) were taken at rest, immediately post exercise and after 15 min recovery. The results showed no significant increase in plasma Cr or muscle total creatine concentration (TCr) after supplementation with Cr. At the end of exercise ATP and CP concentrations had decreased and IMP and lactate concentrations increased in muscle in all groups. Plasma lactate concentration increased during exercise and recovery and plasma uric acid concentration increased during recovery in all groups. No influence could be found in TBV after supplementation with creatine. These results show that creatine supplementation in the dosage used in this study had no influence on muscle metabolic response or TBV.
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PMID:Effect of creatine supplementation on muscle metabolic response to a maximal treadmill exercise test in Standardbred horses. 1109 28

1. The effects of creatine phosphate (CP) and inorganic phosphate (Pi) on sarcoplasmic reticulum (SR) Ca2+ regulation were investigated in mechanically skinned muscle fibres from rat extensor digitorum longus (EDL) muscles. Changes in [Ca2+] were detected using fura-2 fluorescence, during continuous perfusion or when the solution surrounding the preparation was restricted to approximately 6 microl by stopping perfusion. 2. In solutions with 5 mM ATP and 10 mM CP, stopping the flow for 2-3 min had no effect on [Ca2+] within the bath. This suggests that SR Ca2+ uptake is balanced by an efflux under these conditions. 3. In solutions with CP, the introduction of Pi induced a small transient rise in [Ca2+], due to Ca2+ loss from the SR. Following equilibration with solutions containing Pi (> or = 5 mM), a maintained decrease in [Ca2+] occurred when the flow was stopped. This is consistent with calcium phosphate (Ca-Pi) precipitation within the SR, resulting in maintained Ca2+ uptake. 4. In the absence of CP, the [Ca2+] within the bath increased progressively when the flow was stopped. This rise in [Ca2+] was inhibited by an alternative ATP regenerating system comprising phosphoenolpyruvate (PEP) and pyruvate kinase (PK). Therefore, the loss of Ca2+ from the SR may result from local ADP accumulation and the consequent reversal of the SR Ca2+ pump. 5. In the absence of CP, the initial Ca2+ release associated with the introduction of Pi increased markedly. Following prolonged equilibration with solutions containing Pi, a rise in [Ca2+] occurred within the bath when the flow was stopped. Maintained Ca2+ uptake associated with Ca-Pi precipitation was not apparent at any level of Pi tested (1-60 mM), when CP was absent. 6. These results suggest that withdrawal of CP is associated with activation of a SR Ca2+ efflux pathway. This may involve reversal of the SR Ca2+ pump, due to local ADP accumulation. In the absence of CP, the dominant influence of Pi appears to involve further Ca2+ efflux via the SR Ca2+ pump. The possible relevance of these effects to skeletal muscle fatigue is considered.
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PMID:Interdependent effects of inorganic phosphate and creatine phosphate on sarcoplasmic reticulum Ca2+ regulation in mechanically skinned rat skeletal muscle. 1125 Oct 54

We have recently shown that mitochondrial function and energy metabolism are altered in the myocardium as well as in slow and fast locomotor muscles of rats subjected to prolonged congestive heart failure (CHF) suggesting a generalized metabolic myopathy in heart failure. Here, we investigate whether the diaphragm of CHF animals, which experiences both increased work and the general systemic influence of heart failure, will also be susceptible to altered energy metabolism. Biopsies were obtained from the costal diaphragm of failing rats 8 months after aortic banding. A marked increase in type I and type IIa myosin heavy chains at the expense of types IIx and IIb, suggests an adaptation towards a slower phenotype. Glycolytic enzymes decreased in CHF diaphragm with an increase in the H:M lactate dehydrogenase isoenzyme ratio. These results suggest a reorientation of the diaphragm muscle towards a slow, fatigue-resistant phenotype. However, maximal oxidative capacity assessed in saponin-permeabilized fibers in the presence of ADP was considerably reduced in CHF diaphragm (7.7+/-0.4 v 11.8+/-0.7 micromol O2/min/g dry weight in sham P<0.001), suggesting an alteration in oxidative phosphorylation. Furthermore, ADP sensitivity of CHF mitochondria was significantly increased (apparent Km for ADP 308+/-21 v 945+/-106 microM in sham P<0.001), whereas sensitivity to ADP in the presence of creatine was comparable (Km 79+/-12 v 90+/-11 microM in sham). In heart failure, therefore, the diaphragm muscle seems to adapt towards a more slow and economical contraction as a result of increased workload, but this adaptation is limited by the disease-induced altered mitochondrial function.
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PMID:Dual influence of disease and increased load on diaphragm muscle in heart failure. 1127 23

The aim of this study was to examine the effect of the products of ATP hydrolysis on the fatigue process in rat gastrocnemius in vivo. Adult male Sprague-Dawley rats (300-400 g) were anesthetized and ventilated in a custom-built cradle fitted with a force transducer that could be placed into a 7-T NMR magnet. The muscle was stimulated continuously at 2 Hz for 20 min (n = 7). Isometric twitch force increased in the first 4 min of stimulation accompanied by changes in twitch duration (20% increase in relaxation time). Prolonged relaxation was associated with changes in cytosolic pH (6.91 to 6.58), lactate (1.8 to 12.6 micromol/g wet wt), and H(2)PO (7.57 to 13.99 mM). After 4 min, relaxation time, pH, lactate, and H(2)PO returned toward control values as twitch force progressively decreased. No correlation was found between force decline (or twitch broadening) and total phosphate (3 to 23 mM), free [ADP] (18 to 95 microM), free [Mg(2+)] (0.58 to 0.96 mM), or free energy of ATP hydrolysis (-65 to -55 kJ/mol). We conclude that force decline is not due to increased pH and/or H(2)PO but to fatigue of the fast-twitch fibers, possibly linked to glycogen depletion and/or failure of nerve impulse transmission in these fibers.
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PMID:Force reduction uncoupled from pH and H(2)PO(-)(4) in rat gastrocnemius in vivo with continuous 2-Hz stimulation. 1144 55

Magnetic resonance imaging (MRI) and P-31 magnetic resonance spectroscopy (P-31 MRS) provide unique, quantitative data that cannot be obtained from routine laboratory tests. MRI is the method of choice for imaging of muscle abnormalities. It is also a very sensitive technique for localizing nonhomogeneous inflammation in inflammatory myopathies such as dermatomyositis, juvenile dermatomyositis, amyopathic dermatomyositis, polymyositis, and inclusion body myositis. During treatment of inflammatory myopathies, the extent and severity of inflammation may decrease at varying rates, but weakness and fatigue remain serious clinical problems. The metabolic abnormalities detected with P-31 MRS are more persistent and can be used for objective patient evaluation after the disappearance of inflammation and normalization of serum levels of muscle enzymes. With P-31 MRS, biochemical defects are quantitated, including low levels of ATP and phosphocreatine (PCr) and elevated concentrations of ADP and inorganic phosphate (Pi), which may all be related to weakness and fatigue. Thus, MRI and P-31 MRS are useful in assessing the status of patients with inflammatory myopathies during treatment with prednisone and immunosuppressive drugs.
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PMID:Utility of magnetic resonance imaging in the evaluation of patients with inflammatory myopathies. 1147 53

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


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