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

1. The biochemical basis of the slowing of relaxation seen in fatigue has been examined using an isolated mouse soleus preparation. 2. Slowing of relaxation occurred during prolonged tetani under anaerobic conditions when ATP and PC fell and lactate accumulated. 3. Slowing of relaxation was also demonstrated with muscles poisoned with cyanide and iodoacetic acid when there was a fall in ATP and PC but no accumulation of lactate. During a period of anaerobic recovery following a fatiguing tetanus, relaxation became faster at a time when lactate was accumulating in the muscle. 4. It is concluded that the slowing of relaxation in fatigue is not a consequence of lactate accumulation, and a relationship is demonstrated between the ATP content of the muscle and the rate of relaxation in muscles fatigued by prolonged stimulation, 5. Rates of ATP turn-over in fresh muscle, and at intervals throughout a tetanus are consistent with the suggestion that the rate limiting step for myofibrillar ATPase may be directly related to the rate limiting step for the decay of tension during relaxation.
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PMID:Metabolic changes associated with the slowing of relaxation in fatigued mouse muscle. 118 65

1. The role of the myoplasmic free Mg2+ concentration ([Mg2+]i) in fatigue was studied in intact single fibres isolated from mouse skeletal muscle. Fatigue was produced by repeated tetanic stimulation. The fluorescent Mg2+ indicator furaptra was pressure injected into fibres. In vivo calibrations were performed to convert fluorescence signals into [Mg2+]i. 2. [Mg2+]i at rest was 0.78 +/- 0.05 mM (mean +/- S.E.M., n = 14). An increase of the extracellular [Mg2+] from 0.5 to 20 mM resulted in a small elevation of [Mg2+]i (86 microM in 5 min). Removal of extracellular Na+ did not affect [Mg2+]i. An intracellular alkanization of about 0.6 pH units gave a [Mg2+]i reduction of 65 microM. 3. During fatiguing stimulation [Mg2+]i initially remained almost constant and it then suddenly started to rise towards the end of the stimulation period. The onset of the [Mg2+]i rise was always followed by a rapid tension decline. In fatigue [Mg2+]i was approximately twice as high as at rest. 4. Fibres were injected with MgCl2 to study if the rise in [Mg2+]i could explain the tension decline in fatigue. An elevation of [Mg2+]i was accompanied by a tension reduction but the [Mg2+]i for a given tension was generally much higher in rested fibres injected with MgCl2 than in fatigued fibres. Thus the rise in [Mg2+]i as such cannot explain the tension reduction in fatigue. 5. Injection of MgCl2 was also used to assess the intracellular Mg2+ buffering. The mean Mg2+ buffer power (i.e. the ratio of the change in [Mg2+]i to the amount of Mg2+ added) was 0.62. 6. ATP is the quantitatively most important binding site for Mg2+ at rest and ATP breakdown is then a likely source of the [Mg2+]i increase in fatigue. The role of ATP breakdown in the increase of [Mg2+]i was studied with metabolic inhibition: fibres were exposed to iodoacetic acid to inhibit glycolysis and cyanide to inhibit oxidative phosphorylation. The pattern during metabolic inhibition was similar to that observed during fatigue. After remaining almost constant during a lengthy period, [Mg2+]i rose rapidly and this rise preceded a period of rapid tension decline. The fibres thereafter went into rigor and [Mg2+]i stabilized at an elevated level; the mean [Mg2+]i increase in rigor was 1.30 mM. 7. We have used modelling to determine the likely change in the intracellular ATP concentration ([ATP]i) for the observed changes in [Mg2+]i.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Myoplasmic free Mg2+ concentration during repetitive stimulation of single fibres from mouse skeletal muscle. 146 36

1. The performance of skeletal muscle during repetitive stimulation may be limited by the development of an intracellular acidosis due to lactic acid accumulation. To study this, we have measured the intracellular pH (pHi) with the fluorescent indicator BCECF (2',7'-bis(carboxyethyl)-5(6)- carboxyfluorescein) during fatigue produced by repeated, short tetani in intact, single fibres isolated from the mouse flexor brevis muscle. 2. The pHi at rest was 7.33 +/- 0.02 (mean +/- S.E.M., n = 29, 22 degrees C). During fatiguing stimulation pHi initially went alkaline by about 0.03 units (maximum alkalinization after about ten tetani). Thereafter pHi declined slowly and at the end of fatiguing stimulation (tetanic tension reduced to 30% of the original; 0.3Po), pHi was only 0.063 +/- 0.011 units (n = 14) more acid than in control. 3. We considered three possible causes of acidosis being so small in fatigue: (i) a high oxidative capacity so that fatigue occurs without marked production of lactic acid; (ii) an effective transport of H+ or H+ equivalents out of the fibres; a high intracellular buffer power. 4. The oxidative metabolism was inhibited by 2 mM-cyanide in three fibres. After being exposed to cyanide for 5 min without stimulation, the tetanic tension was reduced to about 0.9 Po and pHi was alkaline by about 0.1 units. The fibres fatigued faster in cyanide and the pHi decline in fatigue was more than twice as large as that under control conditions. 5. Inhibition of Na(+)-H+ exchange with amiloride resulted in a slow acidification of rested fibres; resting pHi was not affected by either inhibition of HCO3(-)-Cl- exchange with DIDS (4,4'-diisothiocyanatostilbene-2,2'-disulphonic acid) or inhibition of the lactate transporter with cinnamate. 6. Fibres fatigued in cinnamate displayed a markedly larger acidification (approximately 0.4 pH units) and tension fell more rapidly than under control conditions; inhibition of Na(+)-H+ and HCO3(-)-Cl- exchange did not have any significant effect on fatigue. 7. The intracellular buffer power, assessed by exposing fibres to the weak base trimethylamine, was about 15 mM (pH unit)-1 in a HEPES-buffered solution (non-CO2 or intrinsic buffer power) and about 33 mM (pH unit)-1 in a bicarbonate-buffered solution. Somewhat higher values of the intrinsic buffer power was obtained from changes of the partial pressure of CO2 (PCO2) of the bath solution. Application of lactate or butyrate frequently gave an infinite buffer power, which indicates that powerful pH-regulating mechanisms operate in these cases.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Changes of intracellular pH due to repetitive stimulation of single fibres from mouse skeletal muscle. 152 20

Measurements of the intracellular free concentration of Ca2+ ([Ca2+]i) were performed during fatiguing stimulation of intact, single muscle fibers, which were dissected from a mouse foot muscle and loaded with fura-2. Fatigue, which was produced by repeated 100-Hz tetani, generally occurred in three phases. Initially, tension declined rapidly to approximately 90% of the original tension (0.9 Po) and during this period the tetanic [Ca2+]i increased significantly (phase 1). Then followed a lengthy period of almost stable tension production and tetanic [Ca2+]i (phase 2). Finally, both the tetanic [Ca2+]i and tension fell relatively fast (phase 3). The resting [Ca2+]i rose continuously throughout the stimulation period. A 10-s rest period during phase 3 resulted in a significant increase of both tetanic [Ca2+]i and tension, whereas a 10-s pause during phase 2 did not have any marked effect. Application of caffeine under control conditions and early during phase 2 resulted in a substantial increase of the tetanic [Ca2+]i but no marked tension increase, whereas caffeine applied at the end of fatiguing stimulation (tension depressed to approximately 0.3 Po) gave a marked increase of both tetanic [Ca2+]i and tension. The tetanic [Ca2+]i for a given tension was generally higher during fatiguing stimulation than under control conditions. Fatigue developed more rapidly in fibers exposed to cyanide. In these fibers there was no increase of tetanic [Ca2+]i during phase 1 and the increase of the resting [Ca2+]i during fatiguing stimulation was markedly larger. The present results indicate that fatigue produced by repeated tetani is caused by a combination of reduced maximum tension-generating capacity, reduced myofibrillar Ca2+ sensitivity, and reduced Ca2+ release from the sarcoplasmic reticulum. The depression of maximum tension-generating capacity develops early during fatiguing stimulation and it is of greatest importance for the force decline at early stages of fatigue. As fatigue gets more severe, reduced Ca2+ sensitivity and reduced Ca2+ release become quantitatively more important for the tension decline.
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PMID:Changes of myoplasmic calcium concentration during fatigue in single mouse muscle fibers. 176 71

To evaluate the role of energy state in pulmonary vascular responses to hypoxia, we exposed isolated pig lungs to decreases in inspired PO2 or increases in perfusate NaCN concentration. Lung energy state was assessed by 31P nuclear magnetic resonance spectroscopy or measurement of adenine nucleotides by high-pressure liquid chromatography in freeze-clamped biopsies. In ventilated lungs, inspired PO2 of 200 (normoxia), 50 (hypoxia), and 0 Torr (anoxia) did not change adenine nucleotides but resulted in steady-state pulmonary arterial pressure (Ppa) values of 15.5 +/- 1.4, 30.3 +/- 1.8, and 17.2 +/- 1.9 mmHg, respectively, indicating vasoconstriction during hypoxia and reversal of vasoconstriction during anoxia. In degassed lungs, similar changes in Ppa were observed; however, energy state deteriorated during anoxia. An increase in perfusate NaCN concentration from 0 to 0.1 mM progressively increased Ppa and did not alter adenine nucleotides, whereas 1 mM reversed this vasoconstriction and caused deterioration of energy state. These results suggest that 1) pulmonary vasoconstrictor responses to hypoxia or cyanide occurred independently of whole lung energy state, 2) the inability of the pulmonary vasculature to sustain hypoxic vasoconstriction during anoxia might be associated with decreased energy state in some lung compartment, and 3) atelectasis was detrimental to whole lung energy state.
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PMID:Energy state and vasomotor tone in hypoxic pig lungs. 205 66

The relationship between the redox state and lactate accumulation in contracting human skeletal muscle was investigated. Ten men performed bicycle exercise for 10 min at 40 and 75% of maximal oxygen uptake [VO2(max.)], and to fatigue (4.8 +/- 0.6 min; mean +/- S.E.M.) at 100% VO2(max.). Biopsies from the quadriceps femoris muscle were analysed for NADH, high-energy phosphates and glycolytic intermediates. Muscle NADH was 0.20 +/- 0.02 mmol/kg dry wt. of muscle at rest, and decreased to 0.12 +/- 0.01 (P less than 0.01) after exercise at 40% VO2(max.), but no change occurred in the [lactate]/[pyruvate] ratio. These data, together with previous results on isolated cyanide-poisoned soleus muscle, where NADH increased while [lactate]/[pyruvate] ratio was unchanged [Sahlin & Katz (1986) Biochem. J. 239, 245-248], suggest that the observed changes in muscle NADH occurred within the mitochondria. After exercise at 75 and 100% VO2(max.), muscle NADH increased above the value at rest to 0.27 +/- 0.03 (P less than 0.05) and 0.32 +/- 0.04 (P less than 0.001) mmol/kg respectively. Muscle lactate was unchanged after exercise at 40% VO2(max.), but increased substantially at the higher work loads. At 40% VO2(max.), phosphocreatine decreased by 11% compared with the values at rest, and decreased further at the higher work loads. The decrease in phosphocreatine reflects increased ADP and Pi. It is concluded that muscle NADH decreases during low-intensity exercise, but increases above the value at rest during high-intensity exercise. The increase in muscle NADH is consistent with the hypothesis that the accelerated lactate production during submaximal exercise is due to a limited availability of O2 in the contracting muscle. It is suggested that the increases in NADH, ADP and Pi are metabolic adaptations, which primarily serve to activate the aerobic ATP production, and that the increased anaerobic energy production (phosphocreatine breakdown and lactate formation) is a consequence of these changes.
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PMID:Redox state and lactate accumulation in human skeletal muscle during dynamic exercise. 366 77

When Neurospora mycelium is transferred from a medium containing sucrose to one containing acetate as sole source of carbon, a preferential synthesis of many Krebs cycle, glyoxylate cycle, and associated enzymes occurs. Respiration was inhibited during preferential enzyme synthesis in the following ways. (i) The amount of aeration (shaking) was reduced, (ii) cyanide was added to the culture, (iii) the carbon source, acetate, was removed, (iv) a mutant strain was starved of its Krebs cycle intermediates, and (v) respiration was inhibited by mutation. The effect of this respiratory inhibition on the synthesis of a number of enzymes was measured. It was found that the synthesis of nicotinamide adenine dinucleotide (NAD)-linked glutamate dehydrogenase and phosphoenolpyruvate carboxykinase was significantly less inhibited under conditions of respiratory inhibition than was the synthesis of Krebs cycle, glyoxylate cycle, and most other cell proteins synthesized during the adaptation period. This differential inhibition of enzyme synthesis was almost certainly not due to differential repression by regulatory metabolic end product effectors. Inhibition of mitochondrial respiration under these conditions most likely results in a limitation of the energy supply of the cell. Thus, it is suggested that the inhibition of synthesis of most proteins after inhibition of mitochondrial respiration results from a lack of energy in a utilizable form. Possible reasons to account for the relative insensitivity of NAD-linked glutamate dehydrogenase and phosphoenolpyruvate carboxykinase to inhibition under these conditions are discussed.
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PMID:Selective inhibition of enzyme synthesis under conditions of respiratory inhibition. 509 92

1. ADP inhibits the maximum shortening velocity (V0) in skeletal muscle. [ADP] may increase considerably during contractions and reduce V0 in the absence of energy buffering by phosphocreatine (PCr). We have tested this hypothesis by comparing V0 in long and short tetani produced in situations where PCr buffering is absent. 2. Single, intact muscle fibres were dissected from toe muscles of Xenopus and stimulated by current pulses at 20 degrees C. The test sequence consisted of a 400 ms tetanus, followed after 3 s by a 1400 ms tetanus and after an additional 4 s by a 400 ms tetanus. V0 was measured with slack tests at 200 and 1200 ms, respectively. 3. The PCr system was inactivated in three ways: (i) fatiguing fibres with repeated short tetani; (ii) inhibition of the creatine kinase (CK) reaction with dinitrofluorobenzene; and (iii) inhibition of energy metabolism with iodoacetic acid and cyanide. 4. Under control conditions V0 was similar in all three test tetani. With inactive PCr buffering V0 was about 30% lower in the long tetanus. This slowing recovered fully in the second short tetanus in fatigue and with CK inhibition. 5. Calculations suggest that [ADP] can reach very high levels (about 3 mM) during prolonged contractions in the absence of PCr buffering.
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PMID:Reduced maximum shortening velocity in the absence of phosphocreatine observed in intact fibres of Xenopus skeletal muscle. 771 29

Smoke inhalation injury is a complex of disease processes best understood and treated when defined in terms of the time period after injury. The early phase (0 to 36 hrs) is characterized by diagnosis and treatment of carbon monoxide and cyanide toxicity and by management of early airways edema, bronchorrhea, and bronchoconstriction with aggressive pulmonary toilet. Between 1 and 5 days, the major characteristic is airways mucosal slough, tracheobronchitis, and increasing lung water and impaired gas exchange. Pulmonary toilet and infection control, as well as close management of fluid shifts, is the major treatment. With onset of the inflammation-infection phase, the risk of nosocomial pneumonia increases markedly, as does the impairment in lung function as a result of marked increase in oxygen consumption and CO2 production. Nutrition, stress modification, avoidance of muscle fatigue, and control of infection are the key treatment modalities.
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PMID:Smoke inhalation injury. 792 21

The uptake and accumulation of 1-5 microM cadmium (Cd) was studied in primary cultures of rat renal cortical epithelial cells under protein-free conditions at 4 or 37 degrees C for up to 30 min. The cells were isolated from female rats by collagenase digestion and cultured for 3-7 days. Confluency of the culture, monitored morphologically as well as by total protein content, was achieved on Day 5. Cd accumulation at 1 microM concentration demonstrated an inverse relationship to the cell density; the Cd level in Day 5 culture was only 45% of that in Day 3 culture. In subconfluent cultures (Days 3 and 4) the Cd accumulation was temperature sensitive; on Day 3 the cells accumulated one-third less Cd at 4 degrees C than at 37 degrees C. In comparison, the confluent cells (Day 5) had the same Cd accumulation regardless of the incubation temperature. In these cells, preincubation with cyanide also had no significant effect on Cd accumulation, implying a lack of energy requirement for Cd uptake. As the transport of Cd may involve processes that exist for the essential metal ions, the effect of 30 microM zinc (Zn) and copper (Cu) on the accumulation of 1 microM Cd was studied in Day 5 cultures. Coincubation with Zn caused a 16% reduction in Cd levels at 37 degrees C and even greater reduction (44% of control) at 4 degrees C. Similarly, Cu inhibited Cd accumulation by 26 and 45% at 37 and 4 degrees C, respectively, as compared to the temperature-matched controls. The Vmax for the initial Cd uptake (1 min) was 125 pmol/mg protein/min and the Km was 7 microM. Both Zn and Cu exhibited competitive inhibition kinetics and doubled the Km for Cd uptake. The Ki for Zn and Cu was 23 and 30 microM, respectively. Mercury (Hg) and lead (Pb) were also tested for their ability to affect Cd accumulation. As compared to the controls, 1 microM Hg caused an 11% reduction in Cd level at 37 degrees C. In contrast, 1 microM Pb enhanced Cd accumulation by 20%. However, neither Hg nor Pb had any significant effect on Cd accumulation at 4 degrees C. All four metals had no significant effect on the efflux of Cd from the cells. Thus, these metals affected Cd accumulation by changing its uptake rather than its efflux.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Cadmium uptake by primary cultures of rat renal cortical epithelial cells: influence of cell density and other metal ions. 834 37


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