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

1. The effects of phosphate and protons on the mechanics and energetics of muscle contraction have been investigated using glycerinated rabbit psoas muscle. 2. Fibres were fully activated by addition of Ca2+ (pCa 4-5) at 10 degrees C. The velocities of contraction were measured in isotonic load clamps, and the velocities of unloaded fibres were measured by applying a series of step changes in fibre length. Fibre ATPase activity was monitored using an enzyme system to couple ADP production to reduced nicotinamide-adenine dinucleotide (NADH) and measuring the depletion of NADH by optical density. 3. At pH 7.0 and 3 mM-phosphate, isometric tension (P0) was 13.2 +/- 0.9 N/cm (mean +/- S.E.M., n = 10 observations), the maximum contraction velocity (Vmax) was 1.63 +/- 0.05 lengths/s (n = 5) and the ATPase activity was 1.27 +/- 0.12 s-1 myosin head-1 (n = 35). Increasing phosphate from 3 to 20 mM at pH 7.0 does not affect Vmax, causes a small decrease in the ATPase activity (15-20%) and decreases P0 by approximately 20%. Changing pH from 7 to 6 at 3 mM-phosphate decreases P0 by 45% and both Vmax and ATPase activity by 25-30%. The effects of changing both pH and phosphate were approximately additive for all parameters measured. The inhibition of these parameters by low pH and high concentration of phosphate was reversible. 4. The force-velocity relation was fitted by the Hill equation using a non-linear least-squares method. The value of the parameter which describes the curvature, a/P0, was 0.20. The curvature of the force-velocity relation was not changed by addition of phosphate or by changes in pH. 5. These data provide information on both the kinetics of the actomyosin interaction and on the process of muscle fatigue. The data are consistent with models of cross-bridge kinetics in which phosphate is released within the powerstroke in a step involving a rapid equilibrium between states. The inhibition by protons is more complex, and may involve less specific effects on protein structure. 6. During moderate fatigue of living skeletal muscle, MgATP concentration is known to remain approximately constant at 4 mM, phosphate to increase from 3 to 20 mM, and protons from 0.1 to 1 microM. The data suggest that much of the inhibition of P0 observed during moderate fatigue can be explained by the increased levels of phosphate and protons, and that much of the inhibition of fibre Vmax and ATPase activity can be explained by the increase in protons.
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PMID:The inhibition of rabbit skeletal muscle contraction by hydrogen ions and phosphate. 284 89

There is increasing evidence that platelets play an important role in the pathogenesis of acute ischemic heart disease. Therefore an understanding of factors that influence platelet performance is important. This study was undertaken (1) to characterize during evolving myocardial infarction platelet activity in the peripheral circulation and across the ischemic/infarcting myocardial compartment, the locus of presumed platelet hyperactivity, and (2) to evaluate the effects of prostacyclin (PGI2), a most potent antiplatelet agent and vasodilator. A total of 59 patients with evolving myocardial infarction were studied. Twenty-two patients were instrumented with arterial and coronary sinus catheters and received intravenous infusion of PGI2, 13 +/- 4.5 ng/kg/min (mean +/- SD), for 90 min. In 15 patients with anterior myocardial infarction, transcardiac platelet function and response to PGI2 were studied. Plasma levels of beta-thromboglobulin (beta-TG) and of thromboxane B2 (TxB2), in vivo measures of platelet activity, were elevated three- and 10-fold. 6-Keto-prostaglandin F 1 alpha, the stable end product of PGI2, was less than 10 pg/ml, reflecting a leftward shift of the TxB2/PGI2 ratio. Platelets circulating during evolving myocardial infarction ("ischemic platelets") were hyperaggregable in response to ADP and relatively resistant to PGI2, both in vivo and in vitro. Concentrations of platelet cyclic AMP and the cyclic AMP response to PGI2 were diminished. The platelet hyperreactivity, expressed by plasma beta-TG, platelet aggregation, and PGI2-induced inhibition of aggregation, was most intense early during infarct evolution and decreased with time. The increased platelet performance resulted in "platelet fatigue," indicated by decreased contents of beta-TG of the ischemic platelet and decreased TxA2 production in response to collagen. However, the ischemic platelet produced twice normal TxA2 in response to arachidonic acid (stimulus and substrate), demonstrating a heightened metabolic capacity. TxA2 was produced across the ischemic/infarcting compartment in 10 of 15 patients with anterior myocardial infarction. The antiplatelet effect of PGI2 was greatly diminished. In summary, the data define an abnormal pattern of platelet behavior during evolving myocardial infarction, characterized by a proaggregatory environment, heightened platelet reactivity in both the peripheral and coronary circulation, and relative resistance to PGI2. The clinical consequences of the data are that the patient in the acute phase of myocardial infarction may benefit from suppression of platelet function and requires significantly greater doses of PGI2 than normal subjects.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Systemic and transcardiac platelet activity in acute myocardial infarction in man: resistance to prostacyclin. 293 81

The effect of hyperthyroidism on the fatigue properties of the soleus muscle was investigated in rats treated with T3 (20 micrograms/100 g bw) for 14 (14 d T3) and 30 (30 d T3) days. Maximum tetanic force (Po) was identical in all groups. During 15 minutes of stimulation with 600 ms pulsetrains of 100 Hz at a rate of 60/min, Po declined by 50%, 54%, and 70% in euthyroid, 14 d T3, and 30 d T3 rats, respectively. The results were similar when indirect or direct stimulation was applied. Force recovered to 80% of Po in all groups within five minutes. Whereas relaxation rate and Ca++ transport activity were increased twofold already after 14 days of T3 treatment, myofibrillar ATPase activity (M-ATPase) was only increased in the 30 d T3 group. The decrease in phosphorylation potential ([ATP]/[ADP]f[Pi]) (PP) during stimulation was similar in euthyroid and 14 d T3 rats, but 50% larger in 30 d T3 rats. The latter indicated a higher energy consumption, presumably caused by the M-ATPase. Nevertheless, the PP during fatigue was equal in all groups. The decrease in ATP and the increase in lactate content during fatigue were larger in 14 d T3 and 30 d T3 rats as compared to euthyroid rats, but did not differ between the two hyperthyroid groups. It is concluded that the higher fatigability in the 30 d T3 group cannot be explained by impaired neuromuscular transmission, nor by shortage of energy supply.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Fatigability and recovery of rat soleus muscle in hyperthyroidism. 295 65

The effects of the vasodilating dihydropyridine, felodipine, on tissue concentrations of high-energy phosphates and on oxygen consumption and lactate production in the smooth muscle of the rat portal vein were investigated. Felodipine (100 nM) caused a gradual decrease in the amplitude of the spontaneous phasic contractions in a calcium-containing medium. The mean active force was reduced by about 80% within 15 min. The inhibition of force was associated with reductions in both oxygen consumption and lactate production. No effects of felodipine could be observed in a calcium-free solution. The metabolic rates and force during felodipine inhibition approached those recorded in the calcium-free media. Felodipine (30 nM) did not alter the tissue levels of ATP, ADP, AMP and phosphocreatine. Relaxation by felodipine is thus associated with a decreased energy demand for contraction and, possibly, ionic translocation. The reduced ATP hydrolysis is compensated for by the regeneration of metabolic ATP, thus keeping the cellular levels of high-energy phosphates constant.
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PMID:Effects of felodipine on energy turnover in the rat portal vein. 340 35

The content of glucose 1,6-bisphosphate (G-1,6-P2), an in vitro activator of phosphofructokinase (a rate-limiting enzyme for glycolysis), and the glycolytic rate in skeletal muscle during isometric contraction have been determined. Subjects contracted the knee extensor muscles at two-thirds maximal voluntary force to fatigue. Biopsies from the quadriceps femoris muscle were obtained before and immediately after contraction. G-1,6-P2 increased in all subjects from a mean of 101 +/- 15 (SE) mumol/kg dry wt at rest to 128 +/- 24 at fatigue (P less than 0.05). Muscle glucose did not change significantly, whereas hexosemonophosphates were significantly increased after contraction. The glycogenolytic and glycolytic rate averaged 70.0 +/- 13.8 and 47.3 +/- 6.7 mmol.kg dry wt-1.min-1, respectively, and the glycolytic rate was positively correlated with the accumulation rates of fructose 6-phosphate (F-6-P) (r = 0.95, P less than 0.01) and G-6-P (r = 0.96, P less than 0.01). Phosphocreatine and ATP decreased by 87 and 17%, respectively, whereas ADP increased by 31% after contraction. These data demonstrate that intense, short-term isometric contraction results in an elevation of the muscle content of G-1,6-P2. The increase in G-1,6-P2 could not be accounted for by the side reactions of phosphoglucomutase or phosphofructokinase. It remains to be determined whether the observed increase in G-1,6-P2 is sufficient to account for the high glycolytic rate during intense exercise. The lack of increase in muscle glucose while G-6-P increased (which will inhibit hexokinase) suggests that the debranching enzyme complex was not active during contraction.
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PMID:G-1,6-P2 in human skeletal muscle after isometric contraction. 340 60

To study changes in muscle energy state during prolonged exercise, especially in relation to fatigue, muscle biopsies were obtained from seven healthy males working until exhaustion on a cycle ergometer at 68% (63-74%) of their maximal oxygen uptake. Biopsies were taken at rest, after 15 and 45 min of exercise and at exhaustion, and analysed for ATP, ADP, AMP, inosine monophosphate (IMP) and hypoxanthine content by high performance liquid chromatography (HPLC), and for creatine phosphate (CP), lactate and glycogen by enzymatic fluorometric techniques. Glycogen content at exhaustion was approximately 30% of the pre-exercise level. The CP content decreased steeply during the first 15 min of exercise (P less than 0.01) and continued to decrease during the rest of the exercise period (P less than 0.05). Pronounced increases in contents of IMP (64% P less than 0.001) and hypoxanthine (69%, P less than 0.05) were found when exhaustion was approaching. Furthermore, energy charge [EC; (ATP + 0.5 ADP)/(ATP + ADP + AMP)] was decreased at exhaustion (P less than 0.05). The increases in IMP and hypoxanthine which occurred when exhaustion was approaching during prolonged submaximal exercise together with the decrease in EC during this phase of exercise suggest a failure of the exercising skeletal muscle to regenerate ATP at exhaustion.
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PMID:ATP breakdown products in human skeletal muscle during prolonged exercise to exhaustion. 342 83

Lactic acid is formed and accumulated in the muscle under conditions of high energy demand, rapid fluctuations of the energy requirement and insufficient supply of O2. During intense exercise sustained to fatigue muscle pH decreases to about 6.4-6.6. Force generation does not appear to be limited by the high H+ ion concentration per se but is more related to the PCr level. Phosphofructokinase may be inhibited by high H+ concentration but the inhibition is adequately overcome by increases in the activators AMP and ADP. A high concentration of H+ will decrease PCr by a direct effect on the creatine kinase equilibrium and indirectly by an increase in ADP. The effect of acidosis on glycolysis and on the PCr level will result in a decreased rate of ADP rephosphorylation, and it is suggested that ADP increases transiently above the steady-state level in the contracting muscle fibre. It is further suggested that the function of Na-K-ATPase is impaired by the increase of ADP resulting in an altered ionic balance over the muscle cell membrane. Muscle fatigue is thus considered to be due to an insufficient rate of ADP rephosphorylation resulting in a block in the activation process or in the excitation/contraction coupling.
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PMID:Muscle fatigue and lactic acid accumulation. 347 Oct 61

Muscle phosphorylase deficiency (McArdle's disease) has conventionally been considered a disorder of glycogenolysis, and the associated impairment in oxidative metabolism has been largely overlooked. Muscle glycogen normally is the primary oxidative fuel at exercise work loads requiring more than 75-80% of maximal O2 uptake (VO2max). Evidence is presented to support the hypothesis that a limited flux through the Embden-Myerhof pathway in McArdle's disease reduces the capacity to generate NADH required to support a normal VO2max. The extent of the oxidative defect is substrate dependent; i.e., it can be partially corrected by increasing the availability of alternative oxidative substrates (e.g., glucose, free fatty acids) to working muscle. Experiments employing modification of substrate availability closely link the hyperkinetic circulatory response to exercise (i.e., an abnormally large increase in O2 transport to skeletal muscle) and the premature muscle fatigue and cramping of McArdle patients with their oxidative impairment and suggest that a metabolic common denominator in these abnormal responses may be a pronounced decline in the muscle phosphorylation potential ([ATP]/[ADP][Pi]). The hyperkinetic circulation likely is mediated by the local effects on metabolically sensitive skeletal muscle afferents and vascular smooth muscle of K+, Pi, or adenosine or a combination of these substances released excessively from working skeletal muscle. The premature muscle fatigue and cramping of McArdle patients does not appear to be due to depletion of ATP but is associated with an increased accumulation of Pi and probably ADP in skeletal muscle. Accumulations of Pi and ADP are known to inhibit the myofibrillar, Ca2+, and Na+-K+-ATPase reactions.
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PMID:The pathophysiology of McArdle's disease: clues to regulation in exercise and fatigue. 352 13

During muscular fatigue two metabolites, hydrogen ions (H+) and inorganic phosphate (Pi), increase in concentration. The effect of increase in [H+] has been modeled mathematically for a system containing creatine kinase (EC 2.7.3.2), adenylate kinase (EC 2.7.4.3), and the appropriate concentrations of their substrates. Assuming that no other equilibrium reactions are involved, the result of acidification should be a useful increase in the ratio [ATP]/[ADP]. It is also shown by a reanalysis of earlier 31P NMR studies that the observed combination of increased [H+] and increased [Pi] leads to an increase in the monobasic phosphate concentration [Pi-] that is inversely proportional to the force of contraction. This suggests that Pi- may be a direct inhibitor of the actomyosin ATPase system.
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PMID:Muscular fatigue: effects of hydrogen ions and inorganic phosphate. 353 90

In the process of defining the recruitment of fuel and pathway selection in rainbow trout fast-twitch white skeletal muscle, it was clear that the near-maximal myosin adenosinetriphosphatase activity during a 10-s sprint was supported solely by phosphocreatine hydrolysis. A conservative estimate of the ATP turnover was 188 mumol X g wet wt-1 X min-1. It was not until the rate and force of contraction decreased that the relative contribution of anaerobic glycogenolysis became increasingly important. Over a 10-min period of burst swimming at approximately 120% of maximum aerobic steady-state swimming velocity of trout determined in a Brett-type swim tunnel, fatigue was associated with the near-depletion of glycogen in white muscle. The ATP turnover supported by anaerobic glycogenolysis was 78 mumol X g wet wt-1 X min-1. The glycolytic pathway appeared functional at this time with control sites being identified at hexokinase and phosphofructokinase (PFK-1). PFK-1 did not appear to be inhibited by low muscle pH (pH 6.66). In another exercise protocol lasting 30 min, complete exhaustion was related to glycogen depletion. The sum of all glycolytic intermediates from glucose 6-phosphate to pyruvate at exhaustion decreased by a dramatic 80% compared with the 25% decrease for the 10-min fatigue swimming protocol. This large depletion of glycolytic intermediates was accompanied by an 80% fall in ATP, a 70-80% reduction in the ATP/ADP and phosphorylation potential, and a 2.5-fold increase in the NAD/NADH. Associated with these changes was a marked displacement of the phosphoglycerate kinase (PGK), and the combined glyceraldehyde-3-phosphate dehydrogenase-PGK reactions from thermodynamic equilibrium. As a general conclusion, fatigue and exhaustion should be viewed as a multicomponent biochemical process in response to low glycogen and not leveled at one particular step of the glycolytic pathway.
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PMID:Regulation of anaerobic ATP-generating pathways in trout fast-twitch skeletal muscle. 360 83


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