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Query: UMLS:C0392674 (exhaustion)
 13,658 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Unlike mammalian muscle cells in culture, cultured myotomal muscle cells of Xenopus embryos express ATP-sensitive K+ (KATP) channels. The KATP channels are blocked by internal ATP (half-maximal inhibition K0.5 = 16 microM) and to a lesser extent by internal ADP, are voltage independent, have an inward rectification at positive potentials and are inhibited by glibenclamide (K0.5 = 2 microM). Surprisingly, these KATP channels are not sensitive to K+ channel openers such as cromakalim. Opening of these KATP channels does not occur under normal physiological conditions. It is elicited by metabolic exhaustion of the muscle cell and it precedes the development of an irreversible rigor state. Neither intracellular acidosis nor an increase of intracellular Ca2+ are involved in KATP channel opening. Different types of K+ channels are successively expressed after plating of myotomal muscle cells: (1) sustained delayed-rectifier K+ channels; (2) KATP channels; (3) inward-rectifier K+ channels; (4) transient delayed-rectifier K+ channels. The current density associated with KATP channels far exceeds that of voltage-dependent K+ channels. Innervation controls the expression of these KATP channels. Co-culture of muscle cells with neurons from the neural tube decreases the number of active KATP channels per patch. Similarly, in situ innervated submaxillaris muscle of tadpoles at stage 50-55 has a very low density of KATP channels.
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PMID:Biophysical, pharmacological and developmental properties of ATP-sensitive K+ channels in cultured myotomal muscle cells from Xenopus embryos. 779 38

The inducible isoform of nitric oxide (NO) synthase produces large quantities of NO, a cytotoxic free radical. Recent studies show that treatment with exogenous NO produces DNA strand breaks, activating the nuclear repair enzyme poly(ADP)ribosyltransferase (PARS), which results in ADP ribosylation, NAD+ consumption, and exhaustion of intracellular energy stores. Here we have characterized the cytotoxic effect of endogenous NO and peroxynitrite, a reactive oxidant formed from NO and superoxide. Immunostimulation of J774.2 macrophages with endotoxin resulted in the generation of superoxide (within 1 h) and NO (after 8 h). NO production paralleled an increase in peroxynitrite formation and DNA strand breakage, and a decrease in intracellular NAD+ content and mitochondrial respiration. Inhibition of NO synthase by NG-methyl-L-arginine or S-methyl-isothiourea or inhibition of PARS activity by 3-aminobenzamide or nicotinamide prevented the decrease in mitochondrial respiration and the depletion of NAD+. A similar pattern of free radical formation and cytotoxicity was observed in peritoneal macrophages from endotoxemic rats (formation of NO, superoxide, peroxynitrite, and DNA strand breaks). In vivo treatment with 3-aminobenzamide preserved mitochondrial respiration, NAD+, and ATP. Our data suggest that inflammatory cell injury involved DNA strand breakage and PARS, triggering an energy-consuming, futile repair cycle leading to cellular energy depletion. The active species responsible for the development of DNA strand breaks is peroxynitrite, rather than NO, since exogenous peroxynitrite, but not NO, induces DNA strand breaks. Inhibition of PARS may improve cellular energy homeostasis in patho-physiologic conditions associated with peroxynitrite generation.
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PMID:Peroxynitrite-mediated DNA strand breakage activates poly-adenosine diphosphate ribosyl synthetase and causes cellular energy depletion in macrophages stimulated with bacterial lipopolysaccharide. 859 85

The inducible isoform of nitric oxide synthase (iNOS) produces large quantities of nitric oxide (NO) during inflammation and shock. Recent studies show that the reaction of NO with superoxide yields the cytotoxic oxidant peroxynitrite (ONOO-). An important pathway of ONOO- cytotoxicity involves DNA strand breakage, activation of the nuclear repair enzyme poly(ADP) ribosyltransferase (PARS), and concomitant ADP-ribosylation, NAD+ consumption, and exhaustion of intracellular energy stores. Using quin-2, a calcium chelator, we have investigated the role of calcium in the cytotoxicity elicited by ONOO-. Quin-2 (10-100 microM) ameliorated the suppression of mitochondrial respiration in response to ONOO- (1 mM) in J774 macrophages. Quin-2 at 100 microM, but not at 10 microM, caused a small (20%) inhibition of PARS activity, and did not significantly affect NAD+ depletion. Quin-2 exhibited a slight protective effect against the decrease in mitochondrial respiration in immunostimulated macrophages which endogenously produce ONOO-. These results suggest that the protective effect of quin-2 against the ONOO(-)-induced cellular injury is not due to interference with PARS activation or NAD+ depletion, but rather due to interference with a delayed intracellular event, possibly terminal calcium overload due to inhibition of mitochondrial enzymes and membrane pumps. Inhibition of calcium overload may be a viable experimental strategy to limit ONOO- cytotoxicity.
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PMID:Inhibition of terminal calcium overload protects against peroxynitrite-induced cellular injury in macrophages. 883 86

The reaction of nitric oxide (NO) with superoxide yields the cytotoxic oxidant peroxynitrite, produced during inflammation and shock. A novel pathway of peroxynitrite cytotoxicity involves activation of the nuclear enzyme poly(ADP) ribosyltransferase, and concomitant ADP-ribosylation. NAD+ consumption and exhaustion of intracellular energy stores. In the present report we provide evidence that pre-exposure of J774 macrophages to heat shock reduces peroxynitrite-induced activation of poly(ADP) ribosyltransferase and protects against the peroxynitrite-induced suppression of mitochondrial respiration. The protection was significant at 8 h after heat shock, but was absent at 24 h after heat shock. Thus, the protection showed a temporal correlation with the expression of heat shock protein 70, the expression of which was maximal at 8 h. Exposure to heat shock did not alter the expression of poly(ADP) ribosyltransferase over 24 h. In summary, the heat shock phenotype or heat shock proteins may protect against peroxynitrite induced cytotoxicity.
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PMID:Pre-exposure to heat shock inhibits peroxynitrite-induced activation of poly(ADP) ribosyltransferase and protects against peroxynitrite cytotoxicity in J774 macrophages. 896 Aug 87

It has been generally accepted that the use of oxygen is a major contributor of ATP synthesis in endurance exercise but not in short sprints. In anaerobic exercise, muscle energy is thought to be initially supported by the PCr-ATP system followed by glycolysis, not through mitochondrial oxidative phosphorylation. However, in real exercise practice, we do not know how much of this notion is true when an athlete approaches his/her maximal capacity of aerobic and anaerobic exercise, such as during a graded VO2max test. This study investigates the use of oxygen in aerobic and anaerobic exercise by monitoring oxygen concentration of the vastus lateralis muscle at maximum intensity using Near Infra-red Spectroscopy (NIRS). We tested 14 sprinters from the University of Penn track team, whose competitive events are high jump, pole vault, 100 m, 200 m, 400 m, and 800 m. The Wingate anaerobic power test was performed on a cycle ergometer with 10% body weight resistance for 30 seconds. To compare oxygenation during aerobic exercise, a steady-state VO2max test with a cycle ergometer was used with 25 watt increments every 2 min. until exhaustion. Results showed that in the Wingate test, total power reached 774 +/- 86 watt, about 3 times greater than that in the VO2max test (270 +/- 43 watt). In the Wingate test, the deoxygenation reached approximately 80% of the established maximum value, while in the VO2max test resulted in approximately 36% deoxygenation. There was no delay in onset of deoxygenation in the Wingate test, while in the VO2max test, deoxygenation did not occur under low intensity work. The results indicate that oxygen was used from the beginning of sprint test, suggesting that the mitochondrial ATP synthesis was triggered after a surprisingly brief exercise duration. One explanation is that prior warm-up (unloaded exercise) was enough to provide the mitochondrial substrates; ADP and Pi to activate oxidative phosphorylation by the type II a and type I myocytes. In addition, transmural pressure created by the muscle contraction reduces blood flow, causing relative hypoxia.
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PMID:Muscle deoxygenation in aerobic and anaerobic exercise. 988 77

To examine the effect of ambient temperature on metabolism during fatiguing submaximal exercise, eight men cycled to exhaustion at a workload requiring 70% peak pulmonary oxygen uptake on three separate occasions, at least 1 wk apart. These trials were conducted in ambient temperatures of 3 degrees C (CT), 20 degrees C (NT), and 40 degrees C (HT). Although no differences in muscle or rectal temperature were observed before exercise, both muscle and rectal temperature were higher (P < 0.05) at fatigue in HT compared with CT and NT. Exercise time was longer in CT compared with NT, which, in turn, was longer compared with HT (85 +/- 8 vs. 60 +/- 11 vs. 30 +/- 3 min, respectively; P < 0.05). Plasma epinephrine concentration was not different at rest or at the point of fatigue when the three trials were compared, but concentrations of this hormone were higher (P < 0.05) when HT was compared with NT, which in turn was higher (P < 0.05) compared with CT after 20 min of exercise. Muscle glycogen concentration was not different at rest when the three trials were compared but was higher at fatigue in HT compared with NT and CT, which were not different (299 +/- 33 vs. 153 +/- 27 and 116 +/- 28 mmol/kg dry wt, respectively; P < 0.01). Intramuscular lactate concentration was not different at rest when the three trials were compared but was higher (P < 0.05) at fatigue in HT compared with CT. No differences in the concentration of the total intramuscular adenine nucleotide pool (ATP + ADP + AMP), phosphocreatine, or creatine were observed before or after exercise when the trials were compared. Although intramuscular IMP concentrations were not statistically different before or after exercise when the three trials were compared, there was an exercise-induced increase (P < 0.01) in IMP. These results demonstrate that fatigue during prolonged exercise in hot conditions is not related to carbohydrate availability. Furthermore, the increased endurance in CT compared with NT is probably due to a reduced glycogenolytic rate.
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PMID:Effect of ambient temperature on human skeletal muscle metabolism during fatiguing submaximal exercise. 1006 3

Reactive oxygen species (ROS) are implicated in the mechanism of biological aging and exercise-induced oxidative damage. The present study examined the effect of an acute bout of exercise on intracellular ROS production, lipid and protein peroxidation, and GSH status in the skeletal muscle of young adult (8 mo, n = 24) and old (24 mo, n = 24) female Fischer 344 rats. Young rats ran on a treadmill at 25 m/min and 5% grade until exhaustion (55.4 +/- 2.7 min), whereas old rats ran at 15 m/min and 5% grade until exhaustion (58.0 +/- 2.7 min). Rate of dichlorofluorescin (DCFH) oxidation, an indication of ROS and other intracellular oxidants production in the homogenate of deep vastus lateralis, was 77% (P < 0.01) higher in rested old vs. young rats. Exercise increased DCFH oxidation by 38% (P < 0.09) and 50% (P < 0.01) in the young and old rats, respectively. DCFH oxidation in isolated deep vastus lateralis mitochondria with site 1 substrates was elevated by 57% (P < 0.01) in old vs. young rats but was unaltered with exercise. Significantly higher DCFH oxidation rate was also found in aged-muscle mitochondria (P < 0.01), but not in homogenates, when ADP, NADPH, and Fe(3+) were included in the assay medium without substrates. Lipid peroxidation in muscle measured by malondialdehyde content showed no age effect, but was increased by 20% (P < 0.05) with exercise in both young and old rats. Muscle protein carbonyl formation was unaffected by either age or exercise. Mitochondrial GSH/ GSSG ratio was significantly higher in aged vs. young rats (P < 0.05), whereas exercise increased GSSG content and decreased GSH/GSSG in both age groups (P < 0.05). These data provided direct evidence that oxidant production in skeletal muscle is increased in old age and during prolonged exercise, with both mitochondrial respiratory chain and NADPH oxidase as potential sources. The alterations of muscle lipid peroxidation and mitochondrial GSH status were consistent with these conclusions.
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PMID:Aging and acute exercise enhance free radical generation in rat skeletal muscle. 1040 9

Changes in respiratory activity and in the contents of adenine nucleotides (ATP, ADP, AMP) were studied in cells of the yeast Yarrowia lipolytica during the development of cyanide-resistant respiration. The transition of the yeast from the logarithmic to the stationary growth phase due to exhaustion of glucose was associated with decreased endogenous respiration and with the activation of a cyanide-resistant oxidase. Cyanide activated cell respiration during the stationary growth phase. The cyanide-resistant respiration was inhibited by benzohydroxamic acid (BHA), an inhibitor of the alternative oxidase. In the absence of cyanide, BHA had no effect on the cells which had the cyanide-resistant oxidase. This indicates that the cells do not use the alternative pathway in vivo. The decreased endogenous respiration of the cells was accompanied by decreased contents of adenine nucleotides. Addition of cyanide resulted in a sharp decrease in the content of ATP, in a twofold increase in the content of ADP, and in a fivefold increase in the content of AMP. In the absence of cyanide, BHA had virtually no effect on the contents of adenine nucleotides. The decreased rate of oxygen consumption during the transition of the cells to the stationary growth phase was caused by the decreased activity of the main cytochrome-containing respiratory chain (2,4-dinitrophenol (DNP) stimulated respiration). The alternative oxidase was synthesized in the cell but was inactive. Cyanide stimulated respiration due to activation of the alternative oxidase via the AMP produced. The decrease in the cell content of ATP is suggested to be a factor inducing the synthesis of the alternative oxidase.
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PMID:Development and activation of cyanide-resistant respiration in the yeast Yarrowia lipolytica. 1049 13

1. The present study examined the regulation of human skeletal muscle AMP deamination during intense exercise and quantified muscle accumulation and release of purines during and after intense exercise. 2. Seven healthy males performed knee extensor exercise at 64.3 W (range: 50-70 W) to exhaustion (234 s; 191-259 s). In addition, on two separate days the subjects performed exercise at the same intensity for 30 s and 80 % of exhaustion time (mean, 186 s; range, 153-207 s), respectively. Muscle biopsies were obtained from m.v. lateralis before and after each of the exercise bouts. For the exhaustive bout femoral arterio-venous concentration differences and blood flow were also determined. 3. During the first 30 s of exercise there was no change in muscle adenosine triphosphate (ATP), inosine monophosphate (IMP) and ammonia (NH3), although estimated free ADP and AMP increased 5- and 45-fold, respectively, during this period. After 186 s and at exhaustion muscle ATP had decreased (P < 0.05) by 15 and 19 %, respectively, muscle IMP was elevated (P < 0. 05) from 0.20 to 3.65 and 5.67 mmol (kg dry weight)-1, respectively, and muscle NH3 had increased (P < 0.05) from 0.47 to 2.55 and 2.33 mmol (kg d.w.)-1, respectively. The concentration of H+ did not change during the first 30 s of exercise, but increased (P < 0.05) to 245.9 nmol l-1 (pH 6.61) after 186 s and to 374.5 nmol l-1 (pH 6. 43) at exhaustion. 4. Muscle inosine and hypoxanthine did not change during exercise. In the first 10 min after exercise the muscle IMP concentration decreased (P < 0.05) by 2.96 mmol (kg d.w.)-1 of which inosine and hypoxanthine formation could account for 30 %. The total release of inosine and hypoxanthine during exercise and 90 min of recovery amounted to 1.07 mmol corresponding to 46 % of the net ATP decrease during exercise or 9 % of ATP at rest. 5. The present data suggest that AMP deamination is inhibited during the initial phase of intense exercise, probably due to accumulation of orthophosphate, and that lowered pH is an important positive modulator of AMP deaminase in contracting human skeletal muscle in vivo. Furthermore, formation and release of purines occurs mainly after intense exercise and leads to a considerable loss of nucleotides.
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PMID:AMP deamination and purine exchange in human skeletal muscle during and after intense exercise. 1054 53

A depletion of phosphocreatine (PCr), fall in the total adenine nucleotide pool (TAN = ATP + ADP + AMP), and increase in TAN degradation products inosine 5'-monophosphate (IMP) and hypoxanthine are observed at fatigue during prolonged exercise at 70% maximal O(2) uptake in untrained subjects [J. Baldwin, R. J. Snow, M. F. Carey, and M. A. Febbraio. Am. J. Physiol. 277 (Regulatory Integrative Comp. Physiol. 46): R295-R300, 1999]. The present study aimed to examine whether these metabolic changes are also prevalent when exercise is performed below the blood lactate threshold (LT). Six healthy, untrained humans exercised on a cycle ergometer to voluntary exhaustion at an intensity equivalent to 93 +/- 3% of LT ( approximately 65% peak O(2) uptake). Muscle biopsy samples were obtained at rest, at 10 min of exercise, approximately 40 min before fatigue (F-40 =143 +/- 13 min), and at fatigue (F = 186 +/- 31 min). Glycogen concentration progressively declined (P < 0.01) to very low levels at fatigue (28 +/- 6 mmol glucosyl U/kg dry wt). Despite this, PCr content was not different when F-40 was compared with F and was only reduced by 40% when F was compared with rest (52. 8 +/- 3.7 vs. 87.8 +/- 2.0 mmol/kg dry wt; P < 0.01). In addition, TAN concentration was not reduced, IMP did not increase significantly throughout exercise, and hypoxanthine was not detected in any muscle samples. A significant correlation (r = 0.95; P < 0. 05) was observed between exercise time and glycogen use, indicating that glycogen availability is a limiting factor during prolonged exercise below LT. However, because TAN was not reduced, PCr was not depleted, and no correlation was observed between glycogen content and IMP when glycogen stores were compromised, fatigue may be related to processes other than those involved in muscle high-energy phosphagen metabolism.
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PMID:Skeletal muscle energy metabolism during prolonged, fatiguing exercise. 1060 Nov 87


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