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)

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

A deficit in glucose uptake and a deposition of amyloid beta-peptide (A beta) each occur in vulnerable brain regions in Alzheimer's disease (AD). It is not known whether mechanistic links exist between A beta deposition and impaired glucose transport. We now report that A beta impairs glucose transport in cultured rat hippocampal and cortical neurons by a mechanism involving membrane lipid peroxidation. A beta impaired 3H-deoxy-glucose transport in a concentration-dependent manner and with a time course preceding neurodegeneration. The decrease in glucose transport was followed by a decrease in cellular ATP levels. Impairment of glucose transport, ATP depletion, and cell death were each prevented in cultures pretreated with antioxidants. Exposure to FeSO4, an established inducer of lipid peroxidation, also impaired glucose transport. Immunoprecipitation and Western blot analyses showed that exposure of cultures to A beta induced conjugation of 4-hydroxynonenal (HNE), an aldehydic product of lipid peroxidation, to the neuronal glucose transport protein GLUT3. HNE induced a concentration-dependent impairment of glucose transport and subsequent ATP depletion. Impaired glucose transport was not caused by a decreased energy demand in the neurons, because ouabain, which inhibits Na+/K(+)-ATPase activity and thereby reduces neuronal ATP hydrolysis rate, had little or no effect on glucose transport. Collectively, the data demonstrate that lipid peroxidation mediates A beta-induced impairment of glucose transport in neurons and suggest that this action of A beta may contribute to decreased glucose uptake and neuronal degeneration in AD.
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PMID:Amyloid beta-peptide impairs glucose transport in hippocampal and cortical neurons: involvement of membrane lipid peroxidation. 899 59

1. The present study uses chronic low frequency stimulation of cat medial gastrocnemius (MG) muscle to investigate the relative contribution of innervation ratio to the wide range of motor unit force in large mammalian muscles by reducing the normal variation in muscle fibre cross-sectional area and specific force. 2. Isometric force recordings from isolated and physiologically characterized motor units were made 42-240 days after stimulation. Innervation ratio, fibre area and fibre type (I, II A, II B) were determined in one glycogen-depleted motor unit per muscle. 3. After 42 days of stimulation, all motor units were non-fatigable and were classified as either slow (S) or fast-fatigue resistant (FR). Despite the absence of fast-fatigable (FF) motor units, all three muscle fibre types were present, as identified according to their myofibrillar ATPase reactivity. After 143 days, all motor units and muscle fibres were classified as type S and type I, respectively. 4. A rapid decline in muscle and motor unit force to 30% of normal values after 42 days of chronic stimulation was accounted for by a reduction in muscle fibre area. Fibre areas did not change further with longer periods of stimulation but type II fibres were converted to type I. All stimulated muscle fibres were the size of normal type I fibres; the size of the fibres within single motor units covered the full range of the muscle fibre population. 5. In long-term stimulated muscles (> 100 days) when all muscle fibres were type I and all motor units type S, only differences in innervation ratio could account for the remaining range in motor unit force. Estimates of this range from the minimum and maximum values recorded and from values of tetanic force between the 5th and 95th percentiles indicate that the range in innervation ratio in the MG muscles is at least 15-fold and may be as large as 38-fold. Enumerations of glycogen-depleted muscle fibres from single motor units were consistent with this explanation. 6. The findings provide evidence that there is a wide range of innervation ratios in large muscles, which can account for the large range in motor unit forces in the muscles. Since motor unit force and innervation ratio vary with motoneurone size, these studies provide further support that the size of the peripheral field of innervation of motoneurones is related to their size.
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PMID:Innervation ratio and motor unit force in large muscles: a study of chronically stimulated cat medial gastrocnemius. 913 Jan 74

To examine mechanisms underlying force reduction after the onset of chronic low-frequency (10 Hz) stimulation (CLFS), we exposed rabbit tibialis anterior muscles to various durations of CLFS. To follow changes in isometric contractile properties and electromyographic (EMG) activity, we studied stimulated and contralateral muscles during a terminal test at 10 Hz for 10 min. In addition, activities and protein amounts of the sarcoplasmic reticulum Ca(2+)-ATPase, content of Na(+)-K(+)-ATPase, and expression patterns of triad junction components were examined. Force output and EMG amplitude declined abruptly soon after the onset of stimulation, suggesting refractoriness of a large fiber population. Although twitch force and to a lesser extent EMG activity gradually recovered after stimulation for 6 days and longer, the muscles exhibited profoundly altered properties, i.e., enhanced fatigue resistance, absence of twitch potentiation, and prolonged contraction and relaxation times. These changes were associated with significant increases in Na(+)-K(+)-ATPase concentration and significant decreases in Ca(2+)-ATPase, ryanodine receptor, dihydropyridine receptor, and triadin concentrations over the course of the 20 days of stimulation. Alterations in excitability, Ca2+ handling, and excitation-contraction coupling prior to changes in myofibrillar protein isoforms may thus be responsible for early functional alterations.
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PMID:Early functional and biochemical adaptations to low-frequency stimulation of rabbit fast-twitch muscle. 925 68

We evaluated the hypothesis that impaired sarcolemmal function associated with exaggerated potassium release, impaired potassium uptake, or both may contribute to exertional fatigue and abnormal circulatory responses to exercise in McArdle disease (MD). The cellular mechanism of exertional fatigue and muscle injury in MD is unknown but likely involves impaired function of the ATPases that couple ATP hydrolysis to cellular work, including the muscle sodium potassium pump (Na+K+-ATPase). However, the concentration of muscle Na+K+ pumps in MD is not known, and no studies have related exercise increases in blood potassium concentrations to muscle Na+K+ pump levels. We measured muscle Na+K+ pumps (3H-ouabain binding) and plasma K+ in response to 20 minutes of cycle exercise in six patients with MD and in six sex-, age-, and weight-matched sedentary individuals. MD patients had lower levels of 3H-ouabain binding (231 +/- 18 pmol/g w.w., mean +/- SD, range, 210 to 251) than control subjects (317 +/- 37, range, 266 to 371, p < 0.0004), higher peak increases in plasma potassium in response to 45 +/- 7 W cycle exercise (MD, 1.00 +/- 0.15 mmol/L; control subjects, 0.48 +/- 0.09; p < 0.0001), and mean exercise heart rate responses to exercise that were 45 +/- 12 bpm greater than control subjects. Our results indicate that Na+K+ pump levels are low in MD patients compared with healthy subjects and identify a limitation of potassium reuptake that could result in sarcolemmal failure during peak rates of membrane activation and may promote exaggerated potassium-activated circulatory responses to submaximal exercise. The mechanism of the low Na+K+ pump concentrations in MD is unknown but may relate to deconditioning or to disruption of a close functional relationship between membrane ion transport and glycolysis.
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PMID:Reduced levels of skeletal muscle Na+K+ -ATPase in McArdle disease. 944 49

Biopsies of tibialis anterior muscle were analyzed to determine if increased energy demand of contraction, as indirectly reflected by myofibrillar actomyosin Ca2+ ATPase (qATPase) activity, contributes to symptomatic fatigue in multiple sclerosis (MS). qATPase activity showed a fiber-type effect, IIax > IIa > I. Fiber-type qATPase activity, however, was not different between MS patients and healthy controls. We suggest that fatigue in MS does not reflect increased energy demand of contraction.
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PMID:Muscle fiber type-specific myofibrillar actomyosin Ca2+ ATPase activity in multiple sclerosis. 953 94

The effects of beta-blockade on plasma [K+], muscle excitability and force during fatiguing exercise were examined. Nine healthy males (mean age 22.3+/-1.7 yr) performed a 3-min fatigue protocol that consisted of a sustained submaximal contraction (30% of the maximal voluntary contraction, MVC) of the right quadriceps muscle. Subjects performed the exercise after treatment with either placebo, beta1-selective (metoprolol, 100 mg) or an equipotent dose of non-selective beta1,2-blockade (propranolol, 80 mg, n=6; 100 mg, n=2; 120 mg, n=1) twice daily for 3 days before testing according to a randomized double-blind design. Brachial arterial and femoral venous blood samples were drawn before, during, and for 15 min following the contraction, together with maximal stimulation of the right femoral nerve to evoke a twitch and a compound muscle action potential (M-wave); the M-wave amplitude being used as an index of sarcolemmal excitability. The exercise-induced rise in plasma [K+] did not differ between treatments, but K+ re-uptake during recovery was slower following propranolol. The recovery of the twitch was significantly related to the recovery of plasma [K+] in all trials, but the evoked M-waves were unaffected by either the contraction or the drug treatment. Propranolol resulted in a significantly (P<0.05) greater reduction (51.9+/-7.3%) in MVC following the 3-min contraction compared with metoprolol (40.7+/-3.6%) or placebo (38. 9+/-3.6%). These results suggest that while beta1,2-blockade may significantly affect the recovery of muscle force and K+ homeostasis after fatiguing exercise (presumably through an inhibition of the Na+,K+-ATPase), it does not appear to affect surface membrane excitability.
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PMID:The effect of beta-blockade on plasma potassium concentrations and muscle excitability following static exercise. 964 29

This study examined the effects of fatigue on the functional aspects of the contractile apparatus and sarcoplasmic reticulum (SR). Frog semitendinosus muscles were stimulated to fatigue, and skinned fibers or a homogenate fraction was prepared from both fatigued and rested contralateral muscles. In fatigued fibers, maximal Ca2+-activated force of the contractile apparatus was unaltered, whereas maximal actomyosin-ATPase activity was depressed by 20%. The Ca2+ sensitivity of force was increased, whereas that of actomyosin-ATPase was not altered. Also, the rate constant for tension redevelopment was decreased at submaximal Ca2+ concentration. These latter findings suggest that fatigue slows the dissociation of force-generating myosin cross bridges. Ca2+ uptake and Ca2+-ATPase activity of the SR were depressed by 46 and 21%, respectively, in the fatigued muscles. Fatigue also reduced the rates of SR Ca2+ release evoked by AgNO3 and 4-chloro-m-cresol by 38 and 45%, respectively. During fatigue, the contractile apparatus and SR undergo intrinsic functional alterations. These changes likely result in altered force production and energy consumption by the intact muscle.
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PMID:Functional aspects of skeletal muscle contractile apparatus and sarcoplasmic reticulum after fatigue. 968 40

We investigated the effects of glucose 6-phosphate (G6P) on skeletal muscle contractile apparatus and sarcoplasmic reticulum (SR) function. Using rat extensor digitorum longus fibres, the presence of 5 mM G6P decreased the Ca2+ sensitivity of both force production and actomyosin ATPase (AM-ATPase) activity. Conversely, maximal Ca(2+)-activated force was unaffected while maximal AM-ATPase activity was increased by 37%. In SR vesicles isolated from rat gastrocnemius, G6P markedly altered Ca2+ handling. It increased Ca(2+)-stimulated Ca(2+)-ATPase activity but depressed the net rate of Ca2+ uptake. This latter effect appears to be due to G6P-stimulated Ca2+ release. When G6P was added to Ca(2+)-loaded vesicles, a small, transient release of Ca2+ was elicited. In addition, G6P lowered the threshold for Ca(2+)-induced Ca2+ release but depressed the net rates of both AgNO3- and caffeine-induced releases. It is possible that the accumulation of G6P during muscular activity may adversely affect muscle force production and contribute to the fatigue process via its action on the contractile apparatus and SR.
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PMID:Glucose 6-phosphate alters rat skeletal muscle contractile apparatus and sarcoplasmic reticulum function. 971 71

The myosin heavy chain (MHC) exists as multiple isoforms that are encoded for by a family of genes. The respiratory musculature demonstrates muscle-specific and temporally-dependent changes in MHC isoform expression during maturation. Developmental expression of MHC isoforms correlate well with postnatal changes in actomyosin ATPase activity, specific force generation (P0/CSA), maximum unloaded velocity of shortening (V0) and and fatigue resistance. More specifically, as the expression of MHCneonatal declines and MHC2A, MHC2X, and MHC2B increase, actomyosin ATPase activity, P0/CSA, V0, and muscle fatigability increase. The increase in actomyosin ATPase activity with maturation is partially offset by a postnatal increase in oxidative capacity; however, as fatigue resistance declines with development it is apparent that the energy costs of contraction are not fully matched by an increase in energy production. Developmental transitions in smooth muscle MHC phenotype also occur although their functional importance remains unclear.
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PMID:Myosin heavy chain transitions during development. Functional implications for the respiratory musculature. 973 30


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