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)

Activation of the immune system has been associated with the development of fatigue of unknown cause. We were interested in brain energy stores (e.g., phosphocreatine (PCr) and creatine kinase) after immune activation to investigate whether this system was altered. In this model, fatigue (defined as > 50% reduction in spontaneous running) was induced in C57BL/6 mice after a single injection of Corynebacterium parvum antigen. Maximal fatigue (about 86% reduction on day 10 post injection) was associated with reduced (about 29%) brain PCr/gamma-ATP and increased creatine kinase levels (approximately 31%), suggesting an active process of brain ATP depletion and replenishment. These findings need to be further delineated to establish the relationship between immune activation, reduced brain energy pools and fatigue.
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PMID:Brain energy stores in C57BL/6 mice after C. parvum injection. 1009 58

1. The effect of creatine phosphate (PCr) on sarcoplasmic reticulum (SR) Ca2+ regulation was studied in mechanically skinned skeletal muscle fibres from rat extensor digitorium longus (EDL). Preparations were perfused with solutions mimicking the intracellular milieu and the [Ca2+] within the muscle was monitored continuously using fura-2. 2. Brief application of 40 mM caffeine caused a transient increase in [Ca2+] due to SR Ca2+ release, and an associated tension response. Withdrawal of PCr resulted in (i) a slow transient release of Ca2+ from the SR (ii) a marked prolongation of the descending phase of the caffeine-induced fluorescence ratio transient and (iii) a decrease in the Ca2+ transient amplitude to 69.2 +/- 2.7 % (n = 16) of control responses. 3. Prolongation of the caffeine-induced Ca2+ transient also occurred following application of the SR Ca2+ pump inhibitor cyclopiazonic acid (CPA). This suggests that (i) the descending phase of the caffeine-induced Ca2+ transient is dependent on the rate of Ca2+ uptake by the SR and (ii) prolongation associated with PCr withdrawal may also reflect a decrease in the net Ca2+ uptake rate. 4. The effects of PCr withdrawal were mimicked by addition of the creatine kinase (CK) inhibitor 2,4-dinitro-1-fluorobenzene (DNFB). Hence, reducing the [PCr] may influence SR Ca2+ regulation by limiting local ATP regeneration by endogenous CK. After treatment with DNFB, PCr withdrawal had no effect on the Ca2+ transient, confirming that PCr does not have an additional direct effect on the SR. 5. The Ca2+ efflux associated with PCr withdrawal was insensitive to ryanodine or Ruthenium Red, but was effectively abolished by pretreatment with the SR Ca2+ pump inhibitor cyclopiazonic acid (CPA). This suggests that the Ca2+ efflux associated with PCr withdrawal is independent of the SR Ca2+ channel, but may involve reversal or inhibition of the Ca2+ ATPase. 6. These data suggest that Ca2+ regulation by the SR is strongly dependent on the supply of ATP via endogenous CK. Depletion of PCr may contribute to impaired SR Ca2+ regulation known to occur in intact skeletal muscle under conditions of fatigue.
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PMID:Effects of creatine phosphate on Ca2+ regulation by the sarcoplasmic reticulum in mechanically skinned rat skeletal muscle fibres. 1033 94

The effects of P(i) on sarcoplasmic reticulum (SR) Ca(2+) regulation were studied in mechanically skinned rat skeletal muscle fibers. Brief application of caffeine was used to assess the SR Ca(2+) content, and changes in concentration of Ca(2+) ([Ca(2+)]) within the cytosol were detected with fura 2 fluorescence. Introduction of P(i) (1-40 mM) induced a concentration-dependent Ca(2+) efflux from the SR. In solutions lacking creatine phosphate (CP), the amplitude of the P(i)-induced Ca(2+) transient approximately doubled. A similar potentiation of P(i)-induced Ca(2+) release occurred after inhibition of creatine kinase (CK) with 2,4-dinitrofluorobenzene. In the presence of ruthenium red or ryanodine, caffeine-induced Ca(2+) release was almost abolished, whereas P(i)-induced Ca(2+) release was unaffected. However, introduction of the SR Ca(2+) ATPase inhibitor cyclopiazonic acid effectively abolished P(i)-induced Ca(2+) release. These data suggest that P(i) induces Ca(2+) release from the SR by reversal of the SR Ca(2+) pump but not via the SR Ca(2+) channel under these conditions. If this occurs in intact skeletal muscle during fatigue, activation of a Ca(2+) efflux pathway by P(i) may contribute to the reported decrease in net Ca(2+) uptake and increase in resting [Ca(2+)].
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PMID:Characteristics of phosphate-induced Ca(2+) efflux from the SR in mechanically skinned rat skeletal muscle fibers. 1064 20

The effect of the distribution of rest periods on the efficacy of interval sprint training is analysed. Ten male subjects, divided at random into two groups, performed distinct incremental sprint training protocols, in which the muscle load was the same (14 sessions), but the distribution of rest periods was varied. The 'short programme' group (SP) trained every day for 2 weeks, while the 'long programme' group (LP) trained over a 6-week period with a 2-day rest period following each training session. The volunteers performed a 30-s supramaximal cycling test on a cycle ergometer before and after training. Muscle biopsies were obtained from the vastus lateralis before and after each test to examine metabolites and enzyme activities. Both training programmes led to a marked increase (all significant, P < 0.05) in enzymatic activities related to glycolysis (phosphofructokinase - SP 107%, LP 68% and aldolase - SP 46%, LP 28%) and aerobic metabolism (citrate synthase - SP 38%, LP 28.4% and 3-hydroxyacyl-CoA dehydrogenase - SP 60%, LP 38.7%). However, the activity of creatine kinase (44%), pyruvate kinase (35%) and lactate dehydrogenase (45%) rose significantly (P < 0.05) only in SP. At the end of the training programme, SP had suffered a significant decrease in anaerobic ATP consumption per gram muscle (P < 0.05) and glycogen degradation (P < 0.05) during the post-training test, and failed to improve performance. In contrast, LP showed a marked improvement in performance (P < 0.05) although without a significant increase in anaerobic ATP consumption, glycolysis or glycogenolysis rate. These results indicate that high-intensity cycling training in 14 sessions improves enzyme activities of anaerobic and aerobic metabolism. These changes are affected by the distribution of rest periods, hence shorter rest periods produce larger increase in pyruvate kinase, creatine kinase and lactate dehydrogenase. However, performance did not improve in a short training programme that did not include days for recovery, which suggests that muscle fibres suffer fatigue or injury.
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PMID:The distribution of rest periods affects performance and adaptations of energy metabolism induced by high-intensity training in human muscle. 1084 46

We investigated the use of measurements of serum concentrations of the cardiac proteins troponins I and T as biochemical markers of myocardial cell damage in 80 patients undergoing vascular or major orthopaedic surgery. Holter electrocardiographic monitoring was carried out before surgery and for 3 days after surgery. Blood samples for troponins I and T and creatine kinase-MB isoenzyme were taken on each of these 4 days. Outcome was assessed at 3 months using a patient questionnaire, general practitioner follow-up and case notes review. Silent postoperative myocardial ischaemia was detected in 21 patients; increases in troponins I and T and creatine kinase-MB occurred in four, six and 17 of these patients, respectively. Eight patients suffered major postoperative complications (cardiac death, myocardial ischaemia, congestive cardiac failure, unstable angina and cerebrovascular accident) and 21 minor complications (poorly controlled hypertension needing increased or new additional treatment, palpitations, increased tiredness or shortness of breath in the absence of known respiratory disease). There were no associations between postoperative ischaemia and cardiac protein concentrations. The relative odds for the associations of major adverse outcome at 3 months after surgery and postoperative ischaemia or increased serum concentrations of the three proteins were 5.39 [95% confidence intervals 1.16-27.67] for postoperative ischaemia; 5.64 [1.07-31.00] for creatine kinase-MB isoenzyme; 17.00 [2.20-116.54] for troponin T and 13.20 [1.12-135.00] for troponin I. We found troponin T to be the only prospective marker for both major and minor cardiovascular complications (relative odds 10.65 [1.26-252.88]).
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PMID:Increases in serum concentrations of cardiac proteins and the prediction of early postoperative cardiovascular complications in noncardiac surgery patients. 1155 Jun 85

Eccentric and concentric force and median frequency of the EMG power spectrum were measured during and immediately after maximal eccentric (EE) and concentric (CE) exercise and during the recovery period of 1 week. Eight male subjects performed EE and CE consisting of 100 maximal eccentric and concentric actions with elbow flexors during two separate exercise sessions. When comparing maximal eccentric and concentric actions before the exercises, the average force was higher (P<0.001) in eccentric than in concentric but the average rectified EMG (aEMG) values were the same with the two types of action. The average eccentric force decreased 53.3% after EE and 30.6% after CE, while the average concentric force decreased 49.9% after CE and 38.4% after EE. The recovery was slower after EE. The median frequency (MF) of biceps brachii (BB) in eccentric action decreased during both EE (P<0.01) and CE (P<0.05). It recovered within 2 days of the exercises but was lower again (P<0.01) 7 days after EE. In concentric action MF of BB decreased during CE (P<0.01), while no changes were observed in EE. Blood lactate concentration increased (P<0.001) in both exercises and serum creatine kinase (CK) activity increased in EE only, being significantly higher (P<0.001) 7 days after than before the eccentric exercise. In the absolute scale, the eccentric force in EE decreased more than the concentric force in CE (P<0.01). Fatigue response was action type specific as seen in the greater reduction in the force of the exercise type. MF decreased immediately after both exercises, which may be at least partly related to elevated blood lactate concentration. Eccentric actions led to possible muscle damage as indicated by elevated serum CK and muscle soreness, and therefore to longer recovery as compared to concentric actions. Decreased MF after EE may be indicative of selective damage of the fast twitch fibers in this type of exercise.
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PMID:Force and EMG power spectrum during and after eccentric and concentric fatigue. 1101 39

Dimethylglycine dehydrogenase (DMGDH) (E.C. number 1.5.99.2) is a mitochondrial matrix enzyme involved in the metabolism of choline, converting dimethylglycine to sarcosine. Sarcosine is then transformed to glycine by sarcosine dehydrogenase (E.C. number 1.5.99.1). Both enzymes use flavin adenine dinucleotide and folate in their reaction mechanisms. We have identified a 38-year-old man who has a lifelong condition of fishlike body odor and chronic muscle fatigue, accompanied by elevated levels of the muscle form of creatine kinase in serum. Biochemical analysis of the patient's serum and urine, using (1)H-nuclear magnetic resonance NMR spectroscopy, revealed that his levels of dimethylglycine were much higher than control values. The cDNA and the genomic DNA for human DMGDH (hDMGDH) were then cloned, and a homozygous A-->G substitution (326 A-->G) was identified in both the cDNA and genomic DNA of the patient. This mutation changes a His to an Arg (H109R). Expression analysis of the mutant cDNA indicates that this mutation inactivates the enzyme. We therefore confirm that the patient described here represents the first reported case of a new inborn error of metabolism, DMGDH deficiency.
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PMID:Cloning of dimethylglycine dehydrogenase and a new human inborn error of metabolism, dimethylglycine dehydrogenase deficiency. 1123 3

The influence of an anabolic androgenic steroid (AAS) on thymidine and amino acid uptake in rat hindlimb skeletal muscles during 14 days after a single exhaustive bout of weight lifting was determined. Adult male rats were divided randomly into Control or Steroid groups. Nandrolone decanoate was administered to the Steroid group 1 wk before the exercise bout. [3H]thymidine and [14C]leucine labeling were used to determine the serial changes in cellular mitotic activity, amino acid uptake, and myosin synthesis. Serum creatine kinase (CK) activity, used as a measure of muscle damage, increased 30 and 60 min after exercise in both groups. The total amount of weight lifted was higher, whereas CK levels were lower in Steroid than in Control rats. [3H]thymidine uptake peaked 2 days after exercise in both groups and was 90% higher in Control than in Steroid rats, reflecting a higher level of muscle damage. [14C]leucine uptake was approximately 80% higher at rest and recovered 33% faster postexercise in Steroid than in Control rats. In a separate group of rats, the in situ isometric mechanical properties of the plantaris muscle were determined. The only significant difference was a higher fatigue resistance in the Steroid compared with the Control group. Combined, these results indicate that AAS treatment 1) ameliorates CK efflux and the uptake of [3H]thymidine and enhances the rate of protein synthesis during recovery after a bout of weight lifting, all being consistent with there being less muscle damage, and 2) enhances in vivo work capacity and the in situ fatigue resistance of a primary plantarflexor muscle.
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PMID:Anabolic steroids increase exercise tolerance. 1135 Jul 79

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


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