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)

Mutations in human alpha-skeletal actin have been implicated in causing congenital nemaline myopathy, a disease characterized histopathologically by nemaline bodies in skeletal muscle and manifested in the patient as skeletal muscle weakness. Here we investigate the functional effects of three severe nemaline myopathy mutations (V43F, A138P, and R183G) in human alpha-skeletal actin. Wild-type and mutant actins were expressed and purified from the baculovirus/insect cell expression system. The mutations are located in different subdomains of actin; Val-43 is located in a flexible loop of subdomain 2, Ala-138 is near a hydrophobic cleft in the "hinge" region between subdomains 1 and 3, and Arg-183 is near the nucleotide-binding site. None of the three mutations affected the folding of the actin monomer, the velocity at which skeletal myosin moves actin in an in vitro motility assay, or the relative average isometric force supported by F-actin. Defects in fundamental actomyosin interactions are, therefore, unlikely to account for the muscle weakness observed in affected patients. There were, however, significant changes observed in the polymerization kinetics of V43F and A138P and in the rate of nucleotide release for V43F. No detectable defect was found for R183G. If these subtle changes in polymerization observed in vitro are amplified in the context of the sarcomere, it could in principle be one of the primary insults that triggers the development of nemaline myopathy.
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PMID:Functional effects of nemaline myopathy mutations on human skeletal alpha-actin. 1847 65

The motor neuron disease spinal muscular atrophy (SMA) causes profound muscle weakness that most often leads to early death. At autopsy, SMA is characterized by loss of motor neurons and muscle atrophy, but the initial cellular events that precipitate motor unit dysfunction and loss remain poorly characterized. Here, we examined the function and corresponding structure of neuromuscular junction (NMJ) synapses in a mouse model of severe SMA (hSMN2/delta7SMN/mSmn-/-). Surprisingly, most SMA NMJs remained innervated even late in the disease course; however they showed abnormal synaptic transmission. There was a two-fold reduction in the amplitudes of the evoked endplate currents (EPCs), but normal spontaneous miniature EPC (MEPC) amplitudes. These features in combination indicate reduced quantal content. SMA NMJs also demonstrated increased facilitation suggesting a reduced probability of vesicle release. By electron microscopy, we found a decreased density of synaptic vesicles that is likely to contribute to the reduced release probability. In addition to presynaptic defects, there were postsynaptic abnormalities. EPC and MEPC decay time constants were prolonged because of a slowed switch from the fetal acetylcholine receptor (AChR) gamma-subunit to the adult epsilon-subunit. There was also reduced size of AChR clusters and small myofibers, which expressed an immature pattern of myosin heavy chains. Together these results indicate that impaired synaptic vesicle release at NMJs in severe SMA is likely to contribute to failed postnatal maturation of motor units and muscle weakness.
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PMID:Impaired synaptic vesicle release and immaturity of neuromuscular junctions in spinal muscular atrophy mice. 1915 8

Tropomyosin (Tm) and the troponins (troponin I, troponin T and troponin C) are proteins that work cooperatively to regulate muscle contraction, making actin-myosin interactions sensitive to cytosolic calcium levels. Several isoforms exist for each component in this group, each having a specific expression pattern that enables cardiac, slow skeletal (type 1) and fast skeletal (type 2) muscle fibers to have distinct contractile properties. Mutations in all components of this complex have been associated with skeletal muscle disease. The first disease associations were with nemaline myopathy, but recently other congenital myopathies ('cap disease', congenital fiber type disproportion) and other clinical entities (distal arthrogryposis, multiple pterygium syndrome) have been linked to mutations. A homozygous mutation in CFL2, the gene for muscle cofilin, has been associated with nemaline myopathy in one family to date. Researchers have begun to decipher the mechanisms by which these mutations result in muscle weakness and contractures using a variety of in vitro assays to assess the effects of individual mutations on protein function and on sarcomere dynamics.
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PMID:Skeletal muscle disease due to mutations in tropomyosin, troponin and cofilin. 1918 Oct 92

Hereditary myosin myopathies are a newly emerged group of diseases caused by mutations in skeletal muscle myosin heavy chain (MyHC) genes. The phenotypes of these diseases are varied, ranging from prenatal nonprogressive arthrogrypotic syndromes to adult-onset progressive muscle weakness. They are caused by mutations in skeletal muscle myosin heavy chain (MyHC) genes. Mutations have been reported in two of three MyHC isoforms expressed in adult limb skeletal muscle: type I (slow/beta-cardiac MyHC; MYH7) and type IIa (MYH2). Most of the mutations described in MYH7are associated with hypertrophic/dilated cardiomyopathy, with no skeletal muscle involvement. However, some mutations are associated with two distinct skeletal myopathies, namely Laing distal myopathy and myosin storage myopathy. Although initially thought not to have associated cardiac involvement, recent reports have indicated co-existent cardiac and skeletal muscle disease can occur in both. A myopathy associated with a specific mutation in MYH2 is associated with congenital joint contractures and external ophthalmoplegia. Mutations in embryonic MyHC (MYH3) and perinatal MyHC (MYH8) are associated with distal arthrogryposis syndromes with no or minor muscle weakness. This may be expected in myosin isoforms expressed predominantly during muscle development. Clinical findings, muscle morphology and molecular genetics in hereditary myosin myopathies are summarized in this chapter.
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PMID:Thick filament diseases. 1918 Oct 95

Acquired neuromuscular disorders have been shown to be very common in critically ill patients receiving prolonged mechanical ventilation in the intensive care unit (ICU). Acute Quadriplegic Myopathy (AQM) is a specific acquired myopathy in ICU patients. Patients with AQM are characterized by severe muscle weakness and atrophy of spinal nerve innervated limb and trunk muscles, while cranial nerve innervated craniofacial muscles, sensory and cognitive functions are spared or less affected. The muscle weakness is associated with altered muscle membrane properties and a preferential loss of the motor protein myosin and myosin-associated thick filament proteins. Prolonged mechanical ventilation, muscle unloading, postsynaptic block of neuromuscular transmission, sepsis and systemic corticosteroid hormone treatment have been suggested as important triggering factors in AQM. However, the exact mechanisms underlying the loss of thick filament proteins are not known, though enhanced myofibrillar protein degradation in combination with a downregulation of protein synthesis at the transcriptional level play important roles.
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PMID:Acute quadriplegic myopathy: an acquired "myosinopathy". 1918 Oct 96

Quadriceps muscle weakness is an important component of chronic obstructive pulmonary disease (COPD). We hypothesised that quadriceps weakness would also be a feature of restrictive lung disease due to scoliosis. We studied 10 patients with severe scoliosis (median (interquartile range (IQR)) forced expiratory volume in 1 s (FEV(1))() 35.3 (11)% predicted), 10 patients with severe COPD (FEV(1) 26.5 (9.0)% pred) and 10 healthy age-matched adults. We measured quadriceps strength, exercise capacity and analysed quadriceps muscle biopsies for myosin heavy-chain (MyHC) isoform expression and the presence of oxidative stress. Both groups exhibited quadriceps weakness with median (IQR) maximal voluntary contraction force being 46.0 (17.0) kg, 21.5 (21.0) kg and 31.5 (11.0) kg, respectively (p = 0.02 and 0.04, respectively, for each patient group against controls). Oxidative stress was significantly greater in the quadriceps of both restrictive and COPD patients. The scoliosis patients exhibited a decrease in the proportion of MyHC type I compared with controls; median (IQR) 35.3 (18.5)% compared with 47.7 (9.3)%, p = 0.028. The scoliosis patients also showed an increase in MyHC IIx (26.3 (15.5)% compared with 11.3 (13.0)%, p = 0.01. Quadriceps weakness is a feature of severe scoliosis; the similarities between patients with scoliosis and patients with COPD suggest a common aetiology to quadriceps weakness in both conditions.
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PMID:Quadriceps muscle strength in scoliosis. 2043 81

The transition of reticulocytes into erythrocytes is accompanied by extensive changes in the structure and properties of the plasma membrane. These changes include an increase in shear resistance, loss of surface area, and acquisition of a biconcave shape. The processes by which these changes are effected have remained largely undefined. Here we examine how the expression of 30 distinct membrane proteins and their interactions change during murine reticulocyte maturation. We show that tubulin and cytosolic actin are lost, whereas the membrane content of myosin, tropomyosin, intercellular adhesion molecule-4, glucose transporter-4, Na-K-ATPase, sodium/hydrogen exchanger 1, glycophorin A, CD47, Duffy, and Kell is reduced. The degradation of tubulin and actin is, at least in part, through the ubiquitin-proteasome degradation pathway. In regard to the protein-protein interactions, the formation of membrane-associated spectrin tetramers from dimers is unperturbed, whereas the interactions responsible for the formation of the membrane-skeletal junctions are weaker in reticulocytes, as is the attachment of transmembrane proteins to these structures. This weakness, in part, results from the elevated phosphorylation of 4.1R in reticulocytes, which leads to a decrease in shear resistance by reducing its interaction with spectrin and actin. These observations begin to unravel the mechanistic basis of crucial changes accompanying reticulocyte maturation.
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PMID:Membrane remodeling during reticulocyte maturation. 2003 85

Aberrant transcription and mRNA processing of multiple genes due to RNA-mediated toxic gain-of-function has been suggested to cause the complex phenotype in myotonic dystrophies type 1 and 2 (DM1 and DM2). However, the molecular basis of muscle weakness and wasting and the different pattern of muscle involvement in DM1 and DM2 are not well understood. We have analyzed the mRNA expression of genes encoding muscle-specific proteins and transcription factors by microarray profiling and studied selected genes for abnormal splicing. A subset of the abnormally regulated genes was further analyzed at the protein level. TNNT3 and LDB3 showed abnormal splicing with significant differences in proportions between DM2 and DM1. The differential abnormal splicing patterns for TNNT3 and LDB3 appeared more pronounced in DM2 relative to DM1 and are among the first molecular differences reported between the two diseases. In addition to these specific differences, the majority of the analyzed genes showed an overall increased expression at the mRNA level. In particular, there was a more global abnormality of all different myosin isoforms in both DM1 and DM2 with increased transcript levels and a differential pattern of protein expression. Atrophic fibers in DM2 patients expressed only the fast myosin isoform, while in DM1 patients they co-expressed fast and slow isoforms. However, there was no increase of total myosin protein levels, suggesting that aberrant protein translation and/or turnover may also be involved.
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PMID:Differences in aberrant expression and splicing of sarcomeric proteins in the myotonic dystrophies DM1 and DM2. 2006 28

Pompe disease, a deficiency of lysosomal acid alpha-glucosidase, is a disorder of glycogen metabolism that can affect infants, children, or adults. In all forms of the disease, there is progressive muscle pathology leading to premature death. The pathology is characterized by accumulation of glycogen in lysosomes, autophagic buildup, and muscle atrophy. The purpose of the present investigation was to determine if myofibrillar dysfunction in Pompe disease contributes to muscle weakness beyond that attributed to atrophy. The study was performed on isolated myofibers dissected from severely affected fast glycolytic muscle in the alpha-glucosidase knockout mouse model. Psoas muscle fibers were first permeabilized, so that the contractile proteins could be directly relaxed or activated by control of the composition of the bathing solution. When normalized by cross-sectional area, single fibers from knockout mice produced 6.3 N/cm2 of maximum Ca2+-activated tension compared with 12.0 N/cm2 produced by wild-type fibers. The total protein concentration was slightly higher in the knockout mice, but concentrations of the contractile proteins myosin and actin remained unchanged. Structurally, X-ray diffraction showed that the actin and myosin filaments, normally arranged in hexagonal arrays, were disordered in the knockout muscle, and a lower fraction of myosin cross bridges was near the actin filaments in the relaxed muscle. The results are consistent with a disruption of actin and myosin interactions in the knockout muscles, demonstrating that impaired myofibrillar function contributes to weakness in the diseased muscle fibers.
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PMID:Impaired organization and function of myofilaments in single muscle fibers from a mouse model of Pompe disease. 2022 98

Human point mutations in beta- and gamma-tropomyosin induce contractile deregulation, skeletal muscle weakness, and congenital myopathies. The aim of the present study was to elucidate the hitherto unknown underlying molecular mechanisms. Hence, we recorded and analyzed the X-ray diffraction patterns of human membrane-permeabilized muscle cells expressing a particular beta-tropomyosin mutation (R133W) associated with a loss in cell force production, in vivo muscle weakness, and distal arthrogryposis. Upon addition of calcium, we notably observed less intensified changes, compared with controls, (i) in the second (1/19 nm(-1)), sixth (1/5.9 nm(-1)), and seventh (1/5.1 nm(-1)) actin layer lines of cells set at a sarcomere length, allowing an optimal thin-thick filament overlap; and (ii) in the second actin layer line of overstretched cells. Collectively, these results directly prove that during activation, switching of a positive to a neutral charge at position 133 in the protein partially hinders both calcium- and myosin-induced tropomyosin movement over the thin filament, blocking actin conformational changes and consequently decreasing the number of cross-bridges and subsequent force production.
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PMID:A myopathy-linked tropomyosin mutation severely alters thin filament conformational changes during activation. 2045 3


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