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)

Weight-bearing skeletal muscles change phenotype in response to unloading. Using the hindlimb suspension rat model, we investigated the regulation of myofilament protein isoforms in correlation to contractility. Four weeks of continuous hindlimb unloading produced progressive atrophy and contractility changes in soleus but not extensor digitorum longus muscle. The unloaded soleus muscle also had decreased fatigue resistance. Along with the decrease of myosin heavy chain isoform I and IIa and increase of IIb and IIx, coordinated regulation of thin filament regulatory protein isoforms were observed: gamma- and beta-tropomyosin decreased and alpha-tropomyosin increased, resulting in an alpha/beta ratio similar to that in normal fast twitch skeletal muscle; troponin I and troponin T (TnT) both showed decrease in the slow isoform and increases in the fast isoform. The TnT isoform switching began after 7 days of unloading and TnI isoform showed detectable changes at 14 days while other protein isoform changes were not significant until 28 days of treatment. Correlating to the early changes in contractility, especially the resistance to fatigue, the early response of TnT isoform regulation may play a unique role in the adaptation of skeletal muscle to unloading. When the fast TnT gene expression was upregulated in the unloaded soleus muscle, alternative RNA splicing switched to produce more high molecular weight acidic isoforms, reflecting a potential compensation for the decrease of slow TnT that is critical to skeletal muscle function. The results demonstrate that differential regulation of TnT isoforms is a sensitive mechanism in muscle adaptation to functional demands.
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PMID:Differential regulation of myofilament protein isoforms underlying the contractility changes in skeletal muscle unloading. 1710 8

Muscle spasticity and paresis are conditions that occur secondary to upper motor neuron lesions. The co-existence of decreased motor unit recruitment and intermittent over-activity generates confusion concerning the effect on muscle fiber characteristics. In order to increase the knowledge about the effect of upper motor lesion on capillarization and muscle fiber composition, the biceps brachii muscle from seven young adults with long duration of spastic paresis and seven age-matched controls were analyzed using morphological and enzyme- and immuno-histochemical techniques. The spastic muscles had a 38% lower capillary density (p=0.002), 30% fewer capillaries around each muscle fiber (p=0.02), and 16% fewer capillaries when related to the fiber size (p=0.04). The frequency of fibers expressing myosin heavy chain (MyHC) IIx increased (30% vs. 4%, p=0.006), while the percentage of fibers expressing MyHC I and MyHC IIa, respectively, decreased (22% vs. 46% and 7% vs. 29%, p<0.01). The high proportion of muscle fibers with low oxidative capacity and low capillary supply indicates that biceps brachii muscle from patients with upper motor lesions fatigue more easily than normal controls. We also observed a significantly higher variability in fiber size for fibers expressing MyHC I (p<0.04), and, in three of the subjects, a small amount of small fibers expressing developmental MyHCs was found. These results suggest that, although intermittent stretch reflex contractions might have an impact on the muscle characteristics in spastic paresis, the muscle phenotypic properties are more adapted to decreased voluntary motor unit recruitment.
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PMID:Decreased capillarization and a shift to fast myosin heavy chain IIx in the biceps brachii muscle from young adults with spastic paresis. 1719 19

During human locomotion the ability to generate and sustain mechanical power output is dependent on the organised variability in contractile and metabolic properties of the muscle fibres that comprise the active muscles. In studies of human exercise we have used a micro-dissection technique to obtain fragments of single muscle fibres from needle biopsies before and after exercise. Each fibre fragment is divided into two parts. One part is used to characterize the fibre type in respect of the heavy chain myosin isoform expressed. The other part of the fragment is analysed for high energy phosphate concentrations. Fibres are classified on the basis of expressing either type I, type IIA, or type IIX myosin heavy chain isoforms. It should be noted however that in the type II population many fibres co-express both IIA and the IIX isoforms and we therefore characterize these fibres on the basis of the degree of co-expression. We have used this technique to examine the time course of high energy phosphate concentration and fatigue in different fibre populations during exercise. The progressive reduction of power during maximal sprint efforts may be interpreted as the cumulative effect of metabolic depletion in successive fibre type populations from IIX to IIXa to IIAx to IIA to I. One important application of the micro-dissection technique is that PCr content may also be used as a very sensitive metabolic marker for fibre type recruitment during very short duration concentric, isometric and eccentric exercise.
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PMID:Human muscle fatigue: the significance of muscle fibre type variability studied using a micro-dissection approach. 1724 87

Measurements of human power need to be interpreted in relation to the movement frequency, since that will determine the velocity of contraction of the active muscle and hence the power available according to the power-velocity relationship. Techniques are described which enable movement frequency to be kept constant during human exercise under different conditions. Combined with microdissection and analysis of muscle fibre fragments from needle biopsies obtained pre- and postexercise we have been able 'to take the muscle apart', having measured the power output, including the effect of fatigue, under conditions of constant movement frequency. We have shown that fatigue may be the consequence of a metabolic challenge to a relatively small population of fast fatigue-sensitive fibres, as indicated by [ATP] depletion to approximately 30% of resting values in those fibres expressing myosin heavy chain isoform IIX after just 10 s of maximal dynamic exercise. Since these same fibres will have a high maximal velocity of contraction, they also make a disproportionate contribution to power output in relation to their number, especially at faster movement rates. The microdissection technique can also be used to measure phosphocreatine concentration ([PCr]), which is an exquisitely sensitive indicator of muscle fibre activity; thus, in just seven brief maximal contractions [PCr] is depleted to levels < 50% of rest in all muscle fibre types. The technique has been applied to study exercise at different intensities, and to compare recruitment in lengthening, shortening and isometric contractions, thus yielding new information on patterns of recruitment, energy turnover and efficiency.
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PMID:Structural and functional determinants of human muscle power. 1725 74

The purpose of this investigation was to examine the influence of muscle fiber type composition on the patterns of responses for electromyographic (EMG) and mechanomyographic (MMG) amplitude and mean power frequency (MPF) during a fatiguing submaximal isometric muscle action. Five resistance-trained (mean +/- SD age = 23.2 +/- 3.7 yrs) and five aerobically-trained (mean +/- SD age = 32.6 +/- 5.2 yrs) men volunteered to perform a fatiguing, 30-sec submaximal isometric muscle action of the leg extensors at 50% of the maximum voluntary contraction (MVC). Muscle biopsies from the vastus lateralis revealed that the myosin heavy chain (MHC) composition for the resistance-trained subjects was 59.0 +/- 4.2% Type IIa, 0.1 +/- 0.1% Type IIx, and 40.9 +/- 4.3% Type I. The aerobically-trained subjects had 27.4 +/- 7.8% Type IIa, 0.0 +/- 0.0% Type IIx, and 72.6 +/- 7.8% Type I MHC. The patterns of responses and mean values for absolute and normalized EMG amplitude and MPF during the fatiguing muscle action were similar for the resistance-trained and aerobically-trained subjects. The resistance-trained subjects demonstrated relatively stable levels for absolute and normalized MMG amplitude and MPF across time, but the aerobically-trained subjects showed increases in MMG amplitude and decreases in MMG MPE The absolute MMG amplitude and MPF values for the resistance-trained subjects were also greater than those for the aerobi-cally-trained subjects. These findings suggested that unlike surface EMG, MMG may be a useful noninvasive technique for examining fatigue-related differences in muscle fiber type composition.
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PMID:The influence of muscle fiber type composition on the patterns of responses for electromyographic and mechanomyographic amplitude and mean power frequency during a fatiguing submaximal isometric muscle action. 1771 Oct 40

Calcineurin activation ameliorates the dystrophic pathology of hindlimb muscles in mdx mice and decreases their susceptibility to contraction damage. In mdx mice, the diaphragm is more severely affected than hindlimb muscles and more representative of Duchenne muscular dystrophy. The constitutively active calcineurin Aalpha transgene (CnAalpha) was overexpressed in skeletal muscles of mdx (mdx CnAalpha*) mice to test whether muscle morphology and function would be improved. Contractile function of diaphragm strips and extensor digitorum longus and soleus muscles from adult mdx CnAalpha* and mdx mice was examined in vitro. Hindlimb muscles from mdx CnAalpha* mice had a prolonged twitch time course and were more resistant to fatigue. Because of a slower phenotype and a decrease in fiber cross-sectional area, normalized force was lower in fast- and slow-twitch muscles of mdx CnAalpha* than mdx mice. In the diaphragm, despite a slower phenotype and a approximately 35% reduction in fiber size, normalized force was preserved. This was likely mediated by the reduction in the area of the diaphragm undergoing degeneration (i.e., mononuclear cell and connective and adipose tissue infiltration). The proportion of centrally nucleated fibers was reduced in mdx CnAalpha* compared with mdx mice, indicative of improved myofiber viability. In hindlimb muscles of mdx mice, calcineurin activation increased expression of markers of regeneration, particularly developmental myosin heavy chain isoform and myocyte enhancer factor 2A. Thus activation of the calcineurin signal transduction pathway has potential to ameliorate the mdx pathophysiology, especially in the diaphragm, through its effects on muscle degeneration and regeneration and endurance capacity.
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PMID:Stimulation of calcineurin Aalpha activity attenuates muscle pathophysiology in mdx dystrophic mice. 1819 92

The present study investigated motor unit (MU) loss in a murine model of familial amyotrophic lateral sclerosis (ALS). The fast-twitch tibialis anterior (TA) and medial gastrocnemius (MG) muscles of transgenic SOD1(G93A) and SOD1(WT) mice were studied during the presymptomatic phase of disease progression at 60 days of age. Whole muscle maximum isometric twitch and tetanic forces were 80% lower (P < 0.01) in the TA muscles of SOD1(G93A) compared to SOD1(WT) mice. Enumeration of total MU numbers within TA muscles showed a 60% reduction (P < 0.01) within SOD1(G93A) mice (38 +/- 7) compared with SOD1(WT) controls (95 +/- 12); this was attributed to a lower proportion of the most forceful fast-fatigable (FF) MU in SOD1(G93A) mice, as seen by a significant (P < 0.01) leftward shift in the cumulative frequency histogram of single MU forces. Similar patterns of MU loss and corresponding decreases in isometric twitch force were observed in the MG. Immunocytochemical analyses of the entire cross-sectional area (CSA) of serial sections of TA muscles stained with anti-neural cell adhesion molecule (NCAM) and various monoclonal antibodies for myosin heavy chain (MHC) isoforms showed respective 65% (P < 0.01) and 28% (P < 0.05) decreases in the number of innervated IIB and IID/X muscle fibres in SOD1(G93A), which paralleled the 60% decrease (P < 0.01) in the force generating capacity of individual fibres. The loss of fast MUs was partially compensated by activity-dependent fast-to-slower fibre type transitions, as determined by increases (P < 0.04) in the CSA and proportion of IIA fibres (from 4% to 14%) and IID/X fibres (from 31% to 39%), and decreases (P < 0.001) in the CSA and proportion of type IIB fibres (from 65% to 44%). We conclude that preferential loss of IIB fibres is incomplete at 60 days of age, and is consistent with a selective albeit gradual loss of FF MUs that is not fully compensated by sprouting of the remaining motoneurons that innervate type IIA or IID/X muscle fibres. Our findings indicate that disease progression in fast-twitch muscles of SOD1(G93A) mice involves parallel processes: (1) gradual selective motor axon die-back of the FF motor units that contain large type IIB muscle fibres, and of fatigue-intermediate motor units that innervate type IID/X muscle fibres, and (2) activity-dependent conversion of motor units to those innervated by smaller motor axons innervating type IIA fatigue-resistant muscle fibres.
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PMID:Preferential motor unit loss in the SOD1 G93A transgenic mouse model of amyotrophic lateral sclerosis. 1846 68

Acetylcholinesterase (AChE) plays an essential role in neuromuscular transmission. Not surprisingly, neuromuscular transmission during repetitive nerve stimulation is severely depressed in the AChE knockout mouse (KO). However, whether this deficit in AChE leads to skeletal muscle changes is not known. We have studied the in vitro contractile properties of the postural and locomotor soleus muscles of adult KO and normal (wildtype, WT) mice, and this was completed by histological and biochemical analyses. Our results show that muscle weight, cross-sectional area of muscle fibres and absolute maximal isometric force are all reduced in KO mice compared with WT mice. Of interest, the relative amount of slow myosin heavy chain (MHC-1) in muscle homogenates and the percentage of muscle fibres expressing MHC-1 are decreased in the KO mice. Surprisingly, AChE ablation does not modify twitch kinetics, absolute maximal power, fatigue resistance or citrate synthase activity, despite the reduced number of slow muscle fibres. Thus, a deficit in AChE leads to alterations in the structure and function of muscles but these changes are not simply related to the reduced body weight of KO mice. Our results also suggest that this murine model of congenital myasthenic syndrome with endplate AChE deficiency combines alterations in both neurotransmission and intrinsic muscle properties.
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PMID:Genetic inactivation of acetylcholinesterase causes functional and structural impairment of mouse soleus muscles. 1856 Aug 95

The actin-binding protein alpha-actinin-3 is one of the two isoforms of alpha-actinin that are found in the Z-discs of skeletal muscle. alpha-Actinin-3 is exclusively expressed in fast glycolytic muscle fibers. Homozygosity for a common polymorphism in the ACTN3 gene results in complete deficiency of alpha-actinin-3 in about 1 billion individuals worldwide. Recent genetic studies suggest that the absence of alpha-actinin-3 is detrimental to sprint and power performance in elite athletes and in the general population. In contrast, alpha-actinin-3 deficiency appears to be beneficial for endurance athletes. To determine the effect of alpha-actinin-3 deficiency on the contractile properties of skeletal muscle, we studied isolated extensor digitorum longus (fast-twitch) muscles from a specially developed alpha-actinin-3 knockout (KO) mouse. alpha-Actinin-3-deficient muscles showed similar levels of damage to wild-type (WT) muscles following lengthening contractions of 20% strain, suggesting that the presence or absence of alpha-actinin-3 does not significantly influence the mechanical stability of the sarcomere in the mouse. alpha-Actinin-3 deficiency does not result in any change in myosin heavy chain expression. However, compared with alpha-actinin-3-positive muscles, alpha-actinin-3-deficient muscles displayed longer twitch half-relaxation times, better recovery from fatigue, smaller cross-sectional areas, and lower twitch-to-tetanus ratios. We conclude that alpha-actinin-3 deficiency results in fast-twitch, glycolytic fibers developing slower-twitch, more oxidative properties. These changes in the contractile properties of fast-twitch skeletal muscle from alpha-actinin-3-deficient individuals would be detrimental to optimal sprint and power performance, but beneficial for endurance performance.
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PMID:A gene for speed: contractile properties of isolated whole EDL muscle from an alpha-actinin-3 knockout mouse. 1865 Feb 67

Mice from lines selectively bred for high levels of voluntary wheel running express a high incidence of a small muscle phenotype ('mini-muscles') that may confer an adaptive advantage with respect to endurance-running capacity. Plantar flexors in the mini-muscle phenotype exhibit a high capacity for aerobic activity, including altered enzyme activities, loss of expression of type IIb myosin heavy chain (MHC), increased expression of type I, IIx and IIa MHC, and mechanical performance consistent with slower, more fatigue-resistant muscles. We hypothesized that these changes may accompany enhanced efficiency of contraction, perhaps in support of the enhanced capacity for endurance running. To assess efficiency, we measured work and associated oxygen consumption from isolated soleus and medial gastrocnemius muscles from mice with mini-muscle and normal phenotypes. We also measured the MHC expression of the plantar flexor muscles to better understand the physiological basis of any differences in efficiency. The proportion of the various MHC isoforms in the soleus was shifted toward a slightly faster phenotype in the mini-muscle mice, whereas in the gastrocnemius and plantaris it was shifted toward a markedly slower phenotype, with large reductions in type IIb MHC and large increases in type I, IIa, and IIx MHC. Soleus muscles from normal and mini-muscle mice showed no statistical differences in efficiency, but medial gastrocnemius from mini-muscle mice were significantly less efficient than those from normal mice, despite the distinctly slower MHC phenotype in mini-muscle mice. Thus, based on measures of efficiency from isolated muscles under conditions near optimal for power output, the shift toward a slower phenotype in 'mini' gastrocnemius muscles does not appear to confer advantages directly through increased efficiency. Rather, the slower phenotype may reduce energy used by the muscles and be permissive to enhanced running ability, perhaps by reducing reliance on anaerobic metabolism.
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PMID:Changes in efficiency and myosin expression in the small-muscle phenotype of mice selectively bred for high voluntary running activity. 1928 94


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