Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C1762617 (weakness)
 37,932 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. Raising the intracellular [Ca2+] for 10 s at 23 degrees C abolished depolarization-induced force responses in mechanically skinned muscle fibres of toad and rat (half-maximal effect at 10 and 23 microM, respectively), without affecting the ability of caffeine or low [Mg2+] to open the ryanodine receptor (RyR)/Ca2+ release channels. Thus, excitation-contraction coupling was lost, even though the Ca2+ release channels were still functional. Coupling could not be restored in the duration of an experiment (up to 1 h). 2. The Ca(2+)-dependent uncoupling had a Q10 > 3.5, and was three times slower at pH 5.8 than at pH 7.1. Sr2+ caused similar uncoupling at twenty times higher concentration, but Mg2+, even at 10 mM, was ineffective. Uncoupling was not noticeably affected by removal of ATP or application of protein kinase or phosphatase inhibitors. 3. Confocal laser scanning microscopy showed that the transverse tubular system was sealed in its entirety in mechanically skinned fibres and that its integrity was maintained in uncoupled fibres. Electron microscopy revealed distorted or severed triad junctions and Z-line aberrations in uncoupled fibres. 4. Only when uncoupling was induced at a relatively slow rate (e.g. over 60 s with 2.5 microM Ca2+) could it be prevented by the protease inhibitor leupeptin (1 mM). Immunostaining of Western blots showed no evidence of proteolysis of the RyR, the alpha 1-subunit of dihydropyridine receptor (DHPR) or triadin in uncoupled fibres. 5. Fibres which, whilst intact, were stimulated repeatedly by potassium depolarization with simultaneous application of 30 mM caffeine showed reduced responsiveness after skinning to depolarization but not to caffeine. Rapid release of endogenous Ca2+, or raised [Ca2+] under conditions which minimized the loss of endogenous diffusible myoplasmic molecules from the skinned fibre, caused complete uncoupling. Taken together, these results suggest that Ca(2+)-dependent uncoupling can also occur in intact fibres. 6. This Ca(2+)-dependent loss of depolarization-induced Ca2+ release may play an important feedback role in muscle by stopping Ca2+ release in localized areas where it is excessive and may be responsible for long-lasting muscle fatigue after severe exercise, as well as contributing to muscle weakness in various dystrophies.
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PMID:Raised intracellular [Ca2+] abolishes excitation-contraction coupling in skeletal muscle fibres of rat and toad. 884 31

The mechanisms underlying skeletal muscle functional impairment and structural changes with advanced age are only partially understood. In the present study, we support and expand our theory about alterations in sarcolemmal excitation-sarcoplasmic reticulum Ca2+ release-contraction uncoupling as a primary skeletal muscle alteration and major determinant of weakness and fatigue in mammalian species including humans. To test the hypothesis that the number of RYR1 (ryanodine receptor) uncoupled to DHPR (dihydropyridine receptor) increases with age, we performed high-affinity ligand binding studies in soleus, extensor digitorum longus (EDL) and in a pool of several skeletal muscles consisting of a mixture of fast- and slow-twitch muscle fibers in middle-aged (14-month) and old (28-months) Fisher 344 Brown Norway F1 hybrids rats. The number of DHPR, RYR1, the coupling between both receptors expressed as the DHPR/RYR1 maximum binding capacity, and their dissociation constant for high-affinity ligands were measured. The DHPR/RYR1 ratio was significantly reduced in the three groups of muscles (pool: 1.03 +/- 0.15 and 0.80 +/- 0.11, soleus: 0.44 +/- 0. 12 and 0.26 +/- 0.10, and EDL: 0.95 +/- 0.14 and 0.68 +/- 0.10, for middle-aged and old muscles, respectively). These data support the concept that DHPR-RYR1 uncoupling results in alterations in the voltage-gated sarcoplasmic reticulum Ca2+ release mechanism, decreases in myoplasmic Ca2+ elevation in response to sarcolemmal depolarization, reduced Ca2+ supply to contractile proteins and reduced contraction force with aging.
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PMID:Dihydropyridine receptor-ryanodine receptor uncoupling in aged skeletal muscle. 917 12

A direct peripheral myopathy has been found in organotin intoxication and suggested to be a significant factor in the development of muscle weakness following exposure. In this study, by using the isolated sarcoplasmic reticulum membrane vesicles, we have shown that triphenyltin dose-dependently induced Ca2+ release from the actively and passively loaded sarcoplasmic reticulum vesicles. Triphenyltin induced Ca2+ release in ruthenium red-sensitive and insensitive ways with EC50 values of 75 and 270 microM, respectively. The Ca2+-ATPase activity and Ca2+ uptake of sarcoplasmic reticulum were also inhibited by triphenyltin. Triphenyltin exerted dual effects on the apparent [3H]ryanodine binding. Triphenyltin (0.5-10 microM) dose-dependently potentiated the [3H]ryanodine binding; however, the [3H]ryanodine binding decreased as the concentration of triphenyltin increased. The dissociation of bound [3H]ryanodine was facilitated by triphenyltin. The present study suggested that the internal Ca2+ store of skeletal muscle could be depleted by triphenyltin through the inhibition of the Ca2+ uptake and the induction of Ca2+ release by acting on the Ca2+-ATPase and Ca2+ release channel, also known as the ryanodine receptor, of sarcoplasmic reticulum, respectively. These results could partly explain the development of muscle weakness in organotin intoxication; however, their relevance to the development of peripheral myopathy requires further examination.
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PMID:Induction of calcium release from isolated sarcoplasmic reticulum by triphenyltin. 927 85

Central core disease (CCD) is a well recognized, relatively mild, non- or slowly progressive, dominantly inherited, congenital myopathy due, at least in some families, to mutations in the ryanodine receptor gene on chromosome 19q13.1. We report two unrelated cases with an unusual, early onset congenital myopathy with severe contractures, delayed motor milestones, proximal muscle weakness, normal serum creatine kinase (CK), a non-progressive course, with muscle biopsy findings of central cores and in addition, marked proliferation of connective and adipose tissue, and variation in fibre size. Muscle biopsies from the parents, who were non-consanguineous and healthy, showed minor myopathic changes and uneven staining with oxidative enzymes, but no central cores. The marked histological muscle changes, the distribution of weakness and the non-progressive course of the disease suggest that this is a severe variant of central core disease with secondary dystrophy-like change. The presence of mild changes in the histochemical reactions of biopsies of both parents of these two children supports the hypothesis that they are carriers of a recessive disease gene mutation responsible for this unusually severe form of central core disease.
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PMID:A severe clinical and pathological variant of central core disease with possible autosomal recessive inheritance. 982 76

The mechanism of muscle weakness in myasthenia gravis and its possible relation to antibodies that are directed against the ryanodine receptor (RyR) were studied by the use of the spontaneous thymoma rat (Buffalo/Mna strain). The present study focused on the motor dysfunction as complicated by impaired subcellular machineries and noted particularly in patients with thymus abnormalities. Rats began to develop skeletal muscle weakness soon after birth and worsened progressively. Rats aged 3 months showed a benign thymoma characterized by proliferative lymphocytes; epithelial cells were stained with anti-RyR peptide antibody. The rat serum contained anti-RyR antibodies, but no anti-acetylcholine receptor antibodies. The electrophysiological study in muscle showed a reduction of contractile force without abnormality in synaptic transmission and membrane properties, suggesting a defect in excitation-contraction coupling. Hypothetically, thymic epithelial cells and skeletal muscles share a common RyR antigen, so that anti-RyR antibodies that target the thymic tissue may react with a homologous target in the muscle.
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PMID:Spontaneous thymoma rat as a model for myasthenic weakness caused by anti-ryanodine receptor antibodies. 984 65

Central core disease (CCD) is a human congenital myopathy characterized by fetal hypotonia and proximal muscle weakness that is linked to mutations in the gene encoding the type-1 ryanodine receptor (RyR1). CCD is thought to arise from Ca(2+)-induced damage stemming from mutant RyR1 proteins forming "leaky" sarcoplasmic reticulum (SR) Ca(2+) release channels. A novel mutation in the C-terminal region of RyR1 (I4898T) accounts for an unusually severe and highly penetrant form of CCD in humans [Lynch, P. J., Tong, J., Lehane, M., Mallet, A., Giblin, L., Heffron, J. J., Vaughan, P., Zafra, G., MacLennan, D. H. & McCarthy, T. V. (1999) Proc. Natl. Acad. Sci. USA 96, 4164--4169]. We expressed in skeletal myotubes derived from RyR1-knockout (dyspedic) mice the analogous mutation engineered into a rabbit RyR1 cDNA (I4897T). Here we show that homozygous expression of I4897T in dyspedic myotubes results in a complete uncoupling of sarcolemmal excitation from voltage-gated SR Ca(2+) release without significantly altering resting cytosolic Ca(2+) levels, SR Ca(2+) content, or RyR1-mediated enhancement of dihydropyridine receptor (DHPR) channel activity. Coexpression of both I4897T and wild-type RyR1 resulted in a 60% reduction in voltage-gated SR Ca(2+) release, again without altering resting cytosolic Ca(2+) levels, SR Ca(2+) content, or DHPR channel activity. These findings indicate that muscle weakness suffered by individuals possessing the I4898T mutation involves a functional uncoupling of sarcolemmal excitation from SR Ca(2+) release, rather than the expression of overactive or leaky SR Ca(2+) release channels.
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PMID:Excitation--contraction uncoupling by a human central core disease mutation in the ryanodine receptor. 1127 44

Multi-minicore disease is an autosomal recessive congenital myopathy characterized by the presence of multiple, short-length core lesions (minicores) in both muscle fiber types. These lesions being nonspecific and the clinical phenotype being heterogeneous, multi-minicore disease boundaries remain unclear. To identify its genetic basis, we performed a genome-wide screening in a consanguineous Algerian family in which three children presented in infancy with moderate weakness predominant in axial muscles, pelvic girdle and hands, joint hyperlaxity (hand involvement phenotype), and multiple minicores. We mapped the disease to chromosome 19q13 in this family and, subsequently, in three additional families showing a similar phenotype, with a maximum LOD score of 5.19 for D19S570. This locus was excluded in 16 other multi-minicore disease families with predominantly axial weakness, scoliosis, and respiratory insufficiency ("classical" phenotype). In the Algerian family, we identified a novel homozygous missense mutation (P3527S) in the ryanodine receptor type 1 gene, a positional candidate gene responsible for the autosomal dominant congenital myopathy central core disease. New muscle biopsies from the three patients at adulthood demonstrated typical central core disease with rods; no cores were found in the healthy parents. This subgroup of families linked to 19q13 represents the first variant of central core disease with genetically proven recessive inheritance and transient presentation as multi-minicore disease.
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PMID:A recessive form of central core disease, transiently presenting as multi-minicore disease, is associated with a homozygous mutation in the ryanodine receptor type 1 gene. 1211 81

Malignant hyperthermia (MH) and central core disease (CCD) are autosomal dominant disorders of skeletal muscle. Susceptibility to MH is only apparent after exposure to volatile anesthetics and/or depolarizing muscle relaxants. CCD patients present with diffuse muscular weakness but are also at risk of MH. Mutations in RYR1 (19q13.1), encoding a skeletal muscle calcium release channel (ryanodine receptor), account for the majority of MH and CCD cases. Fifteen RYR1 N-terminal mutations are considered causative of MH susceptibility, five of which are also associated with CCD. In the first extensive UK population survey, eight of 15 mutations were detected in 85 out of 297 (29%) unrelated MH susceptible cases, with G2434R detected in 53 cases (18%). Mutation type was shown to affect significantly MH phenotypes (in vitro contracture test (IVCT) response to caffeine, halothane, and ryanodine). RYR1 mutations associated with both CCD and MH (R163C, R2163H, R2435H) had more severe caffeine and halothane response phenotypes than those associated with MH alone. Mutations near the amino terminal (R163C, G341R) had a relatively greater effect on responses to caffeine than halothane, with a significantly increased caffeine:halothane tension ratio compared to G2434R of the central domain. All phenotypes were more severe in males than females, and were also affected by muscle specimen size and viability. Discordance between RYR1 genotype and IVCT phenotype was observed in seven families (nine individuals), with five false-positives and four false-negatives. This represents the most extensive study of MH patient clinical and genetic data to date and demonstrates that RYR1 mutations involved in CCD are those associated with one end of the spectrum of MH IVCT phenotypes.
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PMID:RYR1 mutations causing central core disease are associated with more severe malignant hyperthermia in vitro contracture test phenotypes. 1212 89

Central core disease (CCD) is an autosomal-dominant human congenital myopathy that is associated with at least 22 different mutations in the skeletal muscle isoform of ryanodine receptor (RyR1). CCD mutations in RyR1 have been proposed to lead to the formation of sarcoplasmic reticulum (SR) Ca(2+) release channels that are excessively leaky to Ca(2+). Although some of the CCD mutations in RyR1 may indeed result in leaky SR Ca(2+) release channels, the leaky-channel hypothesis may not represent the only mechanism for muscle weakness in this disorder. The presence of an alternate mechanism of muscle weakness in CCD is supported by the observation that muscle cells expressing a CCD mutation in the putative pore-forming segment of RyR1 (I4898T) exhibit a functional uncoupling of SR Ca(2+) release from sarcolemmal depolarization. These observations cannot be explained by the leaky-channel hypothesis and indicate that muscle weakness in some forms of CCD arises from an alternate and completely unexpected mechanism, termed "excitation-contraction uncoupling."
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PMID:Altered ryanodine receptor function in central core disease: leaky or uncoupled Ca(2+) release channels? 1216 Oct 72

Changes in intracellular Ca2+-concentration play an important role in the excitation-contraction-relaxation cycle of skeletal muscle. In this review we describe various inheritable muscle diseases to highlight the role of Ca2+-regulatory mechanisms. Upon excitation the ryanodine receptor releases Ca2+ in the cytosol. During and after contraction the sarcoplasmic reticulum (SR) Ca2+ATPase (SERCA) pumps Ca2+ back in the SR resulting in relaxation. An abnormal change in the intracellular Ca2+-concentration results in defective muscle contraction and/or relaxation, which is the cause of various muscle diseases. Malignant hyperthermia (MH) and central core disease (CCD) are both caused by mutations in the ryanodine receptor but show different clinical phenotypes. In MH an acute increase of Ca2+ results in excessive muscle contraction causing rigidity, while in CCD a chronic rise of cytosolic Ca2+ is seen, leading to mitochondrial damage, disorganization of myofibrils and muscle weakness. In Brody disease and also in mitochondrial myopathies, SERCA functions sub optimal causing a prolonged physiological Ca2+-elevation leading to slowing of relaxation. Defective actin-myosin interactions, as in nemaline myopathy and also in mitochondrial myopathies due to ATP-shortage, cause Ca2+-hyposensitivity and slowness of contraction. Information of Ca2+-kinetics in these inherited muscular diseases improves our understanding of the role of calcium in the physiology and pathophysiology of the skeletal muscle cell.
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PMID:Calcium regulation and muscle disease. 1236 86


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