Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0026850 (muscular dystrophy)
 5,870 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Several lines of evidence suggest that free radical mediated injury and oxidative stress may lead to muscle necrosis in the muscular dystrophies, including those related to defects in the dystrophin gene. We have examined muscle cell death using an in vitro assay in which the processes that lead to myofiber necrosis in vivo may be amenable to investigation in a simplified cell culture system. Using myotube cultures from normal and dystrophin-deficient (mdx) mice, we have examined the susceptibilities of the cells to different metabolic stresses. Dystrophin-deficient cells were more susceptible to free radical induced injury when compared to normal cells, but the two populations were equally susceptible to other forms of metabolic stress. The differential response appeared to be specifically related to dystrophin expression since undifferentiated myoblasts (which do not express dystrophin) from normal and mdx mice were equally sensitive to oxidative stress. Thus, the absence of dystrophin appears to render muscle specifically more susceptible to free radical induced injury. These results support the hypothesis that oxidative stress may lead to myofiber necrosis in these disorders. Elucidating the mechanisms leading to cell death may help to explain the variabilities in disease expression that are seen as a function of age, among different muscles, and across species in animals with muscular dystrophy due to dystrophin deficiency.
 ...
PMID:Muscle cells from mdx mice have an increased susceptibility to oxidative stress. 956 86

Deletions and point mutations in the gene encoding the cytoskeletal protein dystrophin and its isoforms cause either the severe progressive myopathy Duchenne muscular dystrophy (DMD) or the milder Becker muscular dystrophy (BMD), largely depending on whether the reading frame is lost or maintained respectively. Frameshift mutations tend to result in a lack of dystrophin at the sarcolemma, destabilization of the membrane and degeneration of skeletal muscle. The mdx mouse is a valuable animal model of DMD as it bears a nonsense point mutation in exon 23 of the murine DMD gene leading to an absence of dystrophin expression in the muscle sarcolemma and muscular dystrophy. This report represents a novel approach to correct dystrophin deficiency at the post-transcriptional level by transfection of muscle cells with antisense RNA. Essentially, 2'- O -methyl oligoribonucleotides (2'OMeRNA) were delivered to the nuclei of primary mdx myoblasts in culture. Dystrophin expression was observed in the sarcolemma of transfected mdx myotubes after transfection by an oligonucleotide complementary to the 3' splice site of murine dystrophin intron 22. Direct sequencing of RT-PCR products from these cells revealed precise splicing of exon 22 to exon 30, skipping the mutant exon and creating a novel in-frame dystrophin transcript. As patients with comparable in-frame internal deletions show relatively mild myopathic symptoms, this may in the future offer a therapeutic approach for DMD, as well as for other inherited disorders.
 ...
PMID:Modification of splicing in the dystrophin gene in cultured Mdx muscle cells by antisense oligoribonucleotides. 961 64

During a gene trap screen, an insertion of the gene trap vector into the dystrophin gene, creating a new allele for the Dmd gene, has been discovered. Because the ROSA beta geo vector was used, the new allele is called Dmd(mdx-beta geo). The insertion occurred 3' of exon 63 of the dystrophin gene, resulting in a mutation that affects all presently known dystrophin isoforms. In contrast to spontaneous or ENU-induced alleles, Dmd(mdx-beta geo) can be used to follow dystrophin expression by staining for beta-galactosidase activity. The high sensitivity of this method revealed additional and earlier expression of dystrophin during embryogenesis than that seen previously with other methods. Dystrophin promoters are active predominantly in the dermamyotome, limb buds, telencephalon, floor plate, eye, liver, pancreas anlagen, and cardiovascular system. Adult Dmd(mdx-beta geo) mice show reporter gene expression in brain, eye, liver, pancreas, and lung. In skeletal and heart muscle, beta-galactosidase activity is not detectable, confirming Western blot data that indicate the absence of the mutant full-length protein in these tissues. Hemizygous Dmd(mdx-beta geo) mice show muscular dystrophy with degenerating muscle fibers, cellular infiltration, and regenerated muscle fibers that have centrally located nuclei. Some mutant animals develop a dilated esophagus, probably due to constriction by the hypertrophic crura of the diaphragm.
 ...
PMID:Dmd(mdx-beta geo): a new allele for the mouse dystrophin gene. 962 97

We used double label immunofluorescence and confocal microscopy to examine the organization of beta-spectrin and dystrophin at the sarcolemma of fast twitch myofibers in the Extensor Digitorum Longus (EDL) of the rat. Both beta-spectrin and dystrophin are concentrated in costameres, a rectilinear sarcolemmal array composed of longitudinal strands and transverse elements overlying Z and M lines. In contrast, intercostameric regions, lying between these linear structures, contain significant levels of dystrophin but little detectable beta-spectrin. The dystrophin-associated proteins, syntrophin and beta-dystroglycan, are also concentrated at costameres but, like dystrophin, are present in intercostameric regions as well. Dystrophin is present at costameres and intercostameric regions in fast twitch muscles of the mouse but is absent from all regions of the sarcolemma in the mdx mouse, which lacks dystrophin. Areas of the sarcolemma near myonuclei also contain dystrophin without beta-spectrin, consistent with the idea that the distribution of dystrophin at the sarcolemma is not dependent on beta-spectrin. We conclude that dystrophin is present under all areas of the sarcolemma. The increased fragility of the sarcolemma in patients with Duchennes muscular dystrophy may be explained in part by the absence of dystrophin not only from costameres, but also from intercostameric regions.
 ...
PMID:Differential distribution of dystrophin and beta-spectrin at the sarcolemma of fast twitch skeletal muscle fibers. 1053 19

Several forms of inherited muscular dystrophy are associated with brain abnormalities and cognitive impairment. One of the most common and severe of these diseases is Duchenne muscular dystrophy (DMD). Dystrophin, the product of the DMD gene, is found in neurones, where it is associated with the postsynaptic membrane. Cognitive impairment in individuals with DMD is thought to be due to an abnormality in the neuronal membrane that is caused by lack of dystrophin. Recent experimental evidence has provided valuable clues in our understanding of the complex molecular neurobiology of muscular dystrophy.
 ...
PMID:The neurobiology of duchenne muscular dystrophy: learning lessons from muscle? 1067 8

Muscular dystrophy is a heterogeneous genetic disease that affects skeletal and cardiac muscle. The genetic defects associated with muscular dystrophy include mutations in dystrophin and its associated glycoproteins, the sarcoglycans. Furthermore, defects in dystrophin have been shown to cause a disruption of the normal expression and localization of the sarcoglycan complex. Thus, abnormalities of sarcoglycan are a common molecular feature in a number of dystrophies. By combining biochemistry, molecular cell biology, and human and mouse genetics, a growing understanding of the sarcoglycan complex is emerging. Sarcoglycan appears to be an important, independent mediator of dystrophic pathology in both skeletal muscle and heart. The absence of sarcoglycan leads to alterations of membrane permeability and apoptosis, two shared features of a number of dystrophies. beta-sarcoglycan and delta-sarcoglycan may form the core of the sarcoglycan subcomplex with alpha- and gamma-sarcoglycan less tightly associated to this core. The relationship of epsilon-sarcoglycan to the dystrophin-glycoprotein complex remains unclear. Animals lacking alpha-, gamma- and delta-sarcoglycan have been described and provide excellent opportunities for further investigation of the function of sarcoglycan. Dystrophin with dystroglycan and laminin may be a mechanical link between the actin cytoskeleton and the extracellular matrix. By positioning itself in close proximity to dystrophin and dystroglycan, sarcoglycan may function to couple mechanical and chemical signals in striated muscle. Sarcoglycan may be an independent signaling or regulatory module whose position in the membrane is determined by dystrophin but whose function is carried out independent of the dystrophin-dystroglycan-laminin axis.
 ...
PMID:Sarcoglycans in muscular dystrophy. 1067 64

Since the identification of dystrophin as the causitive factor in Duchenne muscular dystrophy, there has been substantial progress in understanding the functions and interactions of this protein. Dystrophin has been shown to interact with a group of peripheral- and trans-membrane proteins known as the dystrophin-associated protein complex (DAPC) and mutations in some of the members of this complex have been shown to account for other forms of muscular dystrophy. This review summarizes the experiments using transgenic and knockout mouse models that have defined the roles of dystrophin, and the dystrophin-related protein utrophin at the skeletal muscle membrane and at the neuromuscular junction. These studies are presented in the context of other known interactions at the muscle membrane. Studies of the dystrophin-deficient mdx mouse have lead to a greater understanding of the human disease. Knockouts and transgenics of utrophin have shown this protein to be sufficient to functionally compensate for dystrophin. Dystrophin transgenic mice combined with the mdx mouse have been used to study the function of specific domains of the dystrophin protein. Together these animal models have led to a delineation of protein functions and localization patterns that will be useful for the generation of potential therapies for DMD.
 ...
PMID:Dystrophin and utrophin: genetic analyses of their role in skeletal muscle. 1067 63

Dystrophin coordinates the assembly of a complex of structural and signaling proteins that are required for normal muscle function. A key component of the dystrophin protein complex is alpha-dystrobrevin, a dystrophin-associated protein whose absence results in neuromuscular junction defects and muscular dystrophy. To gain further insights into the role of alpha-dystrobrevin in skeletal muscle, we used the yeast two-hybrid system to identify a novel alpha-dystrobrevin-binding partner called syncoilin. Syncoilin is a new member of the intermediate filament superfamily and is highly expressed in skeletal and cardiac muscle. In normal skeletal muscle, syncoilin is concentrated at the neuromuscular junction, where it colocalizes and coimmunoprecipitates with alpha-dystrobrevin-1. Expression studies in mammalian cells demonstrate that, while alpha-dystrobrevin and syncoilin associate directly, overexpression of syncoilin does not result in the self-assembly of intermediate filaments. Finally, unlike many components of the dystrophin protein complex, we show that syncoilin expression is up-regulated in dystrophin-deficient muscle. These data suggest that alpha-dystrobrevin provides a link between the dystrophin protein complex and the intermediate filament network at the neuromuscular junction, which may be important for the maintenance and maturation of the synapse.
 ...
PMID:Syncoilin, a novel member of the intermediate filament superfamily that interacts with alpha-dystrobrevin in skeletal muscle. 1105 21

Dystrophin coordinates the assembly of a complex of structural and signalling proteins that is required for normal muscle function. A key component of the dystrophin-associated protein complex (DPC) is alpha-dystrobrevin, a dystrophin-related and -associated protein whose absence results in muscular dystrophy and neuromuscular junction defects [1,2]. The current model of the DPC predicts that dystrophin and dystrobrevin each bind a single syntrophin molecule [3]. The syntrophins are PDZ-domain-containing proteins that facilitate the recruitment of signalling proteins such as nNOS (neuronal nitric oxide synthase) to the DPC [4]. Here we show, using yeast two-hybrid analysis and biochemical binding studies, that alpha-dystrobrevin in fact contains two independent syntrophin-binding sites in tandem. The previously undescribed binding site is situated within an alternatively spliced exon of alpha-dystrobrevin, termed the variable region-3 (vr3) sequence, which is specifically expressed in skeletal and cardiac muscle [5,6]. Analysis of the syntrophin-binding region of dystrobrevin reveals a tandem pair of predicted alpha helices with significant sequence similarity. These alpha helices, each termed a syntrophin-binding motif, are also highly conserved in dystrophin and utrophin. Together these data show that there are four potential syntrophin-binding sites per dystrophin complex in skeletal muscle: two on dystrobrevin and two on dystrophin or utrophin. Furthermore, alternative splicing of dystrobrevin provides a mechanism for regulating the stoichiometry of syntrophin association with the DPC. This is likely to have important consequences for the recruitment of specific signalling molecules to the DPC and ultimately for its function.
 ...
PMID:Alternative splicing of dystrobrevin regulates the stoichiometry of syntrophin binding to the dystrophin protein complex. 1106 12

Dystrophin domains are observed in myoblast transplantation experiments and in muscle fibers after somatic reversion in human Duchenne and mdx mouse muscular dystrophy. However, the formation and evolution of dystrophin-positive domains are not well established. Using a muscle satellite cell coculture system, we examined the dynamic restoration of dystrophin expression in dystrophin-deficient myotubes. The dystrophin-positive domains around source nuclei were clearly identified in hybrid myotubes. The occurrence of dystrophin domains was higher in myotubes differentiated from cocultures with a low concentration of normal wild-type satellite cells in relation to dystrophin-deficient satellite cells. At higher seeding ratios, the domain feature of dystrophin expression was more transitory and decreased as myotubes differentiated over time in culture. The average domain size initially increased with the addition of new nuclei by fusion early after differentiation of cocultures. However, separating dystrophin-positive domains according to their number of dystrophin-expressing contributory nuclei showed that diffusion of dystrophin contributed to domain elongation, even in early myotubes and later without fusion of additional nuclei. Diffusion occurred for all domains of one to six wild-type nuclei, and the diffusion rate was higher in domains with larger numbers of nuclei. This dynamic domain feature of dystrophin expression was also related to restoring the organization of dystrophin-associated proteins and acetylcholine receptors to hybrid myotubes. Factors regulating domain formation and diffusion therefore are important considerations in the design of strategies for both myoblast transplantation and gene therapy of Duchenne muscular dystrophy.
 ...
PMID:Dynamic restoration of dystrophin to dystrophin-deficient myotubes. 1115 Sep 69


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>