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Query: UMLS:C0015672 (fatigue)
 51,768 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of the intramuscular injection of bupivacaine hydrochloride on selected morphological characteristics and contractile properties of adult rat extensor digitorum longus muscle was studied. Recovery of normal fiber size was already present 30 days after bupivacaine injection and at 90 days after injection, values of the normalized twitch tension (mN/mg of tissue) and of the fatigue index approached those measured in control muscle, whereas the normalized tetanic tension remained 57% of control. At 7-30 days postinjection, twitch force was decreased by reducing [Ca2+]zero (substituted by Mg2+) or adding Co2+ (5 mmol/L-1). By contrast potentiation of the twitch was recorded in the presence of Cd2+ (2 mmol/L-1). Glycerol treatment only reduced, but did not eliminate twitches developed by muscles 7 days after injection. Present results emphasize the importance of the recovery process in the loss of the susceptibility of the contractile responses to extracellular calcium in bupivacaine-injected muscles. These data may be of interest in the evaluation of functional aspects of muscles in which injections of viral vector or autologous myoblasts have been performed.
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PMID:External calcium dependence of extensor digitorum longus muscle contractility during bupivacaine-induced regeneration. 875 65

1. Raising the intracellular [Ca2+] for 10 s at 23 degrees C abolished depolarization-induced force responses in mechanically skinned muscle fibres of toad and rat (half-maximal effect at 10 and 23 microM, respectively), without affecting the ability of caffeine or low [Mg2+] to open the ryanodine receptor (RyR)/Ca2+ release channels. Thus, excitation-contraction coupling was lost, even though the Ca2+ release channels were still functional. Coupling could not be restored in the duration of an experiment (up to 1 h). 2. The Ca(2+)-dependent uncoupling had a Q10 > 3.5, and was three times slower at pH 5.8 than at pH 7.1. Sr2+ caused similar uncoupling at twenty times higher concentration, but Mg2+, even at 10 mM, was ineffective. Uncoupling was not noticeably affected by removal of ATP or application of protein kinase or phosphatase inhibitors. 3. Confocal laser scanning microscopy showed that the transverse tubular system was sealed in its entirety in mechanically skinned fibres and that its integrity was maintained in uncoupled fibres. Electron microscopy revealed distorted or severed triad junctions and Z-line aberrations in uncoupled fibres. 4. Only when uncoupling was induced at a relatively slow rate (e.g. over 60 s with 2.5 microM Ca2+) could it be prevented by the protease inhibitor leupeptin (1 mM). Immunostaining of Western blots showed no evidence of proteolysis of the RyR, the alpha 1-subunit of dihydropyridine receptor (DHPR) or triadin in uncoupled fibres. 5. Fibres which, whilst intact, were stimulated repeatedly by potassium depolarization with simultaneous application of 30 mM caffeine showed reduced responsiveness after skinning to depolarization but not to caffeine. Rapid release of endogenous Ca2+, or raised [Ca2+] under conditions which minimized the loss of endogenous diffusible myoplasmic molecules from the skinned fibre, caused complete uncoupling. Taken together, these results suggest that Ca(2+)-dependent uncoupling can also occur in intact fibres. 6. This Ca(2+)-dependent loss of depolarization-induced Ca2+ release may play an important feedback role in muscle by stopping Ca2+ release in localized areas where it is excessive and may be responsible for long-lasting muscle fatigue after severe exercise, as well as contributing to muscle weakness in various dystrophies.
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PMID:Raised intracellular [Ca2+] abolishes excitation-contraction coupling in skeletal muscle fibres of rat and toad. 884 31

We have presented an assay for measuring the rate of sarcoplasmic reticulum (SR) Ca2+ uptake and Ca2+ release in skeletal muscle homogenates using the fluorescent Ca2+ probe Fura-2. Using this assay, we investigated the effects of an elevated temperature (40 degrees C) and lowered pH (6.8), two factors proposed to be involved in skeletal muscle fatigue, on SR Ca2+ uptake. The EDL muscle was found to have a higher rate of Ca2+ uptake than the soleus (34%). Exposure of the muscles to a raised temperature, but not a reduced pH, resulted in a reduction in the rate of Ca2+ uptake in both the EDL and soleus homogenates. This uptake process was blocked by cyclopiazonic acid (CPA) a specific inhibitor of the major transport protein of the sarcoplasmic reticulum, the Ca(2+)-ATPase. Calcium release was induced using AgNO3 after loading of the vesicles during the uptake process. It was found that AgNO3 was only effective in producing Ca2+ release in the EDL muscles. The soleus muscles did not release Ca2+ under varying [Mg2+] or with Hg2+ substitution for Ag+, suggesting that fast- and slow-twitch muscle fibres require different conditions for maximum Ca2+ release, or that different isoforms of the Ca2+ release channels are present in the different fibres.
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PMID:A method for measuring sarcoplasmic reticulum calcium uptake in the skeletal muscle using Fura-2. 886 73

Squid (Lolliguncula brevis) were exercised at increasing swimming speeds to allow us to analyze the correlated changes in intracellular metabolic, acid-base, and energy status of the mantle musculature. Beyond a critical swimming velocity of 1.5 mantle lengths/s, an intracellular acidosis developed that was caused by an initial base loss from the cells, the onset of respiratory acidification, and, predominantly, octopine formation. The acidosis was correlated with decreasing levels of phospho-L-arginine and, thus, supported ATP buffering at the expense of the phosphagen. Monohydrogenphosphate, the actual substrate of glycogen phosphorylase accumulated, enabling glycogen degradation, despite progressive acidosis. In addition to octopine, succinate, and glycerophosphate accumulation, the onset of acidosis characterizes the critical velocity and indicates the transition to a non-steady-state time-limited situation. Accordingly, swimming above the critical velocity caused cellular energy levels (in vivo Gibbs free energy change of ATP hydrolysis) to fall. A minimal value was reached at about -45 kJ/mol. Model calculations demonstrate that changes in free Mg2+ levels only minimally affect ATP free energy, but minimum levels are relevant in maintaining functional concentrations of Mg(2+)-complexed adenylates. Model calculations also reveal that phosphagen breakdown enabled L. brevis to reach swimming speeds about three times higher than the critical velocity. Comparison of two offshore squid species (Loligo pealei and Illex illecebrosus) with the estuarine squid L.brevis indicates that the latter uses a strategy to delay the exploitation of high-energy phosphates and protect energy levels at higher than the minimum levels (-42 kJ/mol) characterizing fatigue in the other species. A more economical use of anaerobic resources and an early reduction in performance may enable L. brevis to tolerate more extreme environmental conditions in shallow estuarine waters and even hypoxic environments and to prevent a fatal depletion of energy stores.
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PMID:Metabolic and energy correlates of intracellular pH in progressive fatigue of squid (L. brevis) mantle muscle. 894 80

Mechanically skinned fibre preparations from the extensor digitorum longus muscle of the rat were used to test whether a rise in myoplasmic [NH+4] in the range 2-10 mM interferes with the mechanism of excitation-contraction coupling in fast-twitch mammalian muscle. Under our conditions (pH 7.10, Mg2+ 1 mM, temperature 23 degrees C), [NH+4] up to 10 mM had little effect on the Ca(+)-activated force and on the peak of the t-system depolarization-induced force response. However, the duration of the depolarization-induced force response was decreased significantly at [NH+4] > or = 2 mM. From these data we conclude that the intracellular accumulation of NH+4 is not likely to play a major role in fatigue. Nevertheless, the build up of NH+4 during fatigue, may have a significant inhibitory effect on the force output by decreasing the duration of the t-system depolarization-induced activation of the contractile apparatus.
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PMID:Effects of ammonium ions on the depolarization-induced and direct activation of the contractile apparatus in mechanically skinned fast-twitch skeletal muscle fibres of the rat. 899 80

Skeletal muscle fatigue develops gradually during all forms of exercise, and develops more rapidly in heart failure patients. The fatigue mechanism is still not known, but is most likely localized to the muscle cells themselves. During high intensity exercise the perturbations of the Na+ and K+ balance in the exercising muscle favour depolarization, smaller action potentials and inexcitability. The Na+, K+ pump becomes strongly activated and limits, but does not prevent the rise in extracellular Na+, K+ pump concentration and intracellular Na+ concentration. However, by virtue of its electrogenic property the pump may contribute in maintaining excitability and contractility by keeping the cells more polarized than the ion gradients predict. With prolonged exercise perturbations of Na+ and K+ are smaller and fatigue may be associated with altered cellular handling of Ca2+ and Mg2+. Release of Ca2+ from the sarcoplasmic reticulum (SR) is reduced in the absence of changes of the cellular content of Ca2+ and Mg2+. In heart failure several clinical reports indicate severe electrolyte perturbations in skeletal muscle. However, in well controlled studies small or insignificant changes are found. We conclude that with high intensity exercise perturbations of Na+ and K+ in muscle cells may contribute to fatigue, whereas with endurance type of exercise and in heart failure patients the skeletal muscle fatigue is more likely to reside in the intracellular control of Ca2+ release and reuptake.
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PMID:Skeletal muscle fatigue in normal subjects and heart failure patients. Is there a common mechanism? 957 67

1. Single mechanically skinned fibres from rat extensor digitorum longus (EDL) muscles were used to investigate the mechanisms underlying inorganic phosphate (Pi) movements between the myoplasm and the sarcoplasmic reticulum (SR). Force transients elicited by caffeine/low Mg2+ application were used to assess the rate of Pi-induced inhibition of SR Ca2+ release and the subsequent recovery of Ca2+ release following removal of myoplasmic Pi. 2. Myoplasmic Pi reduced SR Ca2+ release in a concentration- and time-dependent manner. A 10 s exposure to 10, 20 and 50 mM myoplasmic Pi reduced SR Ca2+ release by 12 +/- 9, 29 +/- 5 and 82 +/- 5 %, respectively. 3. Removal of myoplasmic ATP at the time of Pi exposure significantly increased the rate and extent of SR Ca2+ release inhibition. For example, Ca2+ release was reduced by 86 +/- 6 % (n = 6) after 20 s exposure to 20 mM Pi in the absence of ATP compared with only 47 +/- 5 % (n = 5) in the presence of ATP. 4. The half and full recovery times for SR Ca2+ release following washout of myoplasmic Pi were 35 s and approximately 7 min, respectively. Recovery of Ca2+ release was unaffected by the absence of ATP during washout of Pi but was prevented when fibres were washed in the presence of high myoplasmic Pi (30 mM). Neither the Pi transporter blocker phenylphosphonic acid (PHPA) nor the anion channel blockers anthracene-9-carboxylic acid (9-AC) and 4,4'-diisothiocyanatostilbene-2,2'-disulphonic acid (DIDS) affected the rate of recovery of SR Ca2+ release. 5. These results show that Pi entry and exit from the SR occur primarily through a passive pathway that is insensitive to well-known anion channel blockers. Pi inhibition of SR Ca2+ release appears to be a complicated phenomenon influenced by the rate of Pi movement across the SR as well as by the rate, extent and species of Ca2+-Pi precipitate formation in the SR lumen. The more rapid inhibitory effect of Pi in the absence of myoplasmic ATP suggests that Pi may inhibit SR Ca2+ release more efficiently during the later stages of fatigue.
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PMID:Mechanisms underlying phosphate-induced failure of Ca2+ release in single skinned skeletal muscle fibres of the rat. 972 20

Despite progress in leukemia therapy, only 20-30% of patients with acute myelogenous leukemia (AML) are cured. 1-beta-D-arabinofuranosylcytosine- and topoisomerase II-reactive drugs are the primary therapeutic agents used. The aim of this study was to evaluate the potential activity of tallimustine in leukemia. In this study, we first investigated the efficacy and toxic effects of tallimustine, a distamycin-A derivative, in a human leukemia model in severe combined immunodeficient (SCID) mice. On the basis of its dramatic activity in this preclinical study, a Phase I study of tallimustine at a starting dose of 300 microgram/m2/day for 3 days every 3-4 weeks was conducted in patients with refractory or relapsed leukemia. In SCID mice grafted with a human myelomonocytic leukemia cell line, tallimustine resulted in complete remission of disease in most mice at tolerable dosages ranging from 0.86 to 3.0 mg/kg/day for 3 days and was combined effectively and safely with a 2-day schedule of high-dose ara-C. In the Phase I study, 26 patients with refractory or relapsed leukemia were treated. The maximum tolerated dose was 900 microgram/m2/day for 3 days every 3-4 weeks. This dose was 3 times higher than the maximum tolerated dose in solid tumors and was limited by severe mucositis. Magnesium and potassium wasting were also observed, but other side effects (fatigue and gastrointestinal) were minor. Two (8%) patients with AML achieved complete remission and two achieved hematological improvement with persistent thrombocytopenia. The results of this study indicate that tallimustine has promising activity in AML. Future studies may combine tallimustine with other agents known to be active against AML, and investigate its activity in other hematological malignancies. The recommended Phase II single-agent dose of tallimustine is 750-900 microgram/m2/day for 3 days, and combination studies may start at 50-66% of this dose schedule. The SCID mouse model of human leukemia may be promising in the preclinical evaluation and selection of potential antileukemic agents.
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PMID:Tallimustine, an effective antileukemic agent in a severe combined immunodeficient mouse model of adult myelogenous leukemia, induces remissions in a phase I study. 981 37

1. The effect on sarcoplasmic reticulum (SR) function of exposure to high intracellular [Ca2+] was studied in mechanically skinned fibres from the extensor digitorum longus muscle of the rat, using caffeine to assay the SR Ca2+ content. 2. A 15 s exposure to 50 microM Ca2+ irreversibly reduced the ability of the SR to load/retain Ca2+ and completely abolished depolarization-induced Ca2+ release, whereas a 90 s exposure to 10 microM Ca2+ had no detectable effect on either function. The reduction in net SR Ca2+ uptake: (a) was near-maximal with treatment at 50 microM Ca2+, (b) was unrelated to voltage-sensor function, and (c) persisted unchanged for > 20 min. The reduction was primarily due to a threefold increase in leakage of Ca2+ out of the SR. This increased leakage was not substantially blocked by the presence of 10 mM Mg2+ or 2 microM Ruthenium Red. 3. The adverse effect on SR function of exposure to high [Ca2+] could also be observed by the reduction in the ability of the SR to maintain a low [Ca2+] within the skinned fibre in the face of elevated [Ca2+] in the bathing solution. When bathed in a solution with approximately 1.5 microM Ca2+ (0.75 mM CaEGTA-EGTA), skinned fibres produced only low force responses for many minutes, but after high [Ca2+] treatment (15 s exposure to 50 microM Ca2+) they showed large, steady or oscillatory force responses. 4. These findings indicate that, in addition to uncoupling the Ca2+ release channels from the voltage sensors, exposure of skinned fibres to high [Ca2+] causes a persistent increase in resting Ca2+ efflux from the SR. Such efflux in an intact fibre would alter the distribution of Ca2+ between the SR, the cytoplasm and the extracellular solution. These results may be relevant to the basis of low-frequency fatigue and possibly other conditions in muscle.
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PMID:High intracellular [Ca2+] alters sarcoplasmic reticulum function in skinned skeletal muscle fibres of the rat. 1045 93

Mechanisms of fatigue were studied in single muscle fibres of the cane toad (Bufo marinus) in which force, intracellular calcium ([Ca2+]i), [Mg2+]i, glycogen and the rapidly releasable Ca2+ from the sarcoplasmic reticulum (SR) were measured. Fatigue was produced by repeated tetani continued until force had fallen to 50%. Two patterns of fatigue in the absence of glucose were studied. In the first fatigue run force fell to 50% in 8-10 min. Fatigue runs were then repeated until force fell to 50% in < 3 min in the final fatigue run. Addition of extracellular glucose after the final fatigue run prolonged a subsequent fatigue run. In the first fatigue run peak tetanic [Ca2+]i initially increased and then declined and at the time when force had fallen to 50% tetanic [Ca2+]i was 54+/-5% of initial value. In the final fatigue run force and peak tetanic [Ca2+]i declined more rapidly but to the same level as in first fatigue runs. At the end of the first fatigue run, the rapidly releasable SR Ca2+ store fell to 46+/-6% of the pre-fatigue value. At the end of the final fatigue run the rapidly releasable SR Ca2+ store was 109+/-16% of the pre-fatigue value. In unstimulated fibres the nonwashable glycogen content was 176+/-30 mmol glycosyl units/l fibre. After one fatigue run the glycogen content was 117+/-17 mmol glycosyl units/l fibre; at the end of the final fatigue run the glycogen content was reduced to 85+/-9 mmol glycosyl units/l fibre. [Mg2+]i did not change significantly at the end of fatigue in either the first or the final fatigue run suggesting that globally-averaged ATP does not decline substantially in either pattern of fatigue. These results suggest that different mechanisms are involved in the decline of tetanic [Ca2+]i in first compared to final fatigue runs. The SR Ca2+ store is reduced in first fatigue runs; this is not the case for the final fatigue run which is associated with a decline in glycogen and possibly related to either a non-metabolic effect of glycogen or a spatially-localised metabolic decline.
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PMID:Intracellular calcium during fatigue of cane toad skeletal muscle in the absence of glucose. 1112 39


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