Dystrophin: A muscle protein localized in surface membranes which is the product of the Duchenne/Becker muscular dystrophy gene. Individuals with Duchenne muscular dystrophy usually lack dystrophin completely while those with Becker muscular dystrophy have dystrophin of an altered size. It shares features with other cytoskeletal proteins such as SPECTRIN and alpha-actinin but the precise function of dystrophin is not clear. One possible role might be to preserve the integrity and alignment of the plasma membrane to the myofibrils during muscle contraction and relaxation. MW 400 kDa.Muscular Dystrophy, Duchenne: An X-linked recessive muscle disease caused by an inability to synthesize DYSTROPHIN, which is involved with maintaining the integrity of the sarcolemma. Muscle fibers undergo a process that features degeneration and regeneration. Clinical manifestations include proximal weakness in the first few years of life, pseudohypertrophy, cardiomyopathy (see MYOCARDIAL DISEASES), and an increased incidence of impaired mentation. Becker muscular dystrophy is a closely related condition featuring a later onset of disease (usually adolescence) and a slowly progressive course. (Adams et al., Principles of Neurology, 6th ed, p1415)Algorithms: A procedure consisting of a sequence of algebraic formulas and/or logical steps to calculate or determine a given task.Muscular Dystrophies: A heterogeneous group of inherited MYOPATHIES, characterized by wasting and weakness of the SKELETAL MUSCLE. They are categorized by the sites of MUSCLE WEAKNESS; AGE OF ONSET; and INHERITANCE PATTERNS.Hominidae: Family of the suborder HAPLORHINI (Anthropoidea) comprising bipedal primate MAMMALS. It includes modern man (HOMO SAPIENS) and the great apes: gorillas (GORILLA GORILLA), chimpanzees (PAN PANISCUS and PAN TROGLODYTES), and orangutans (PONGO PYGMAEUS).Mice, Inbred mdx: A strain of mice arising from a spontaneous MUTATION (mdx) in inbred C57BL mice. This mutation is X chromosome-linked and produces viable homozygous animals that lack the muscle protein DYSTROPHIN, have high serum levels of muscle ENZYMES, and possess histological lesions similar to human MUSCULAR DYSTROPHY. The histological features, linkage, and map position of mdx make these mice a worthy animal model of DUCHENNE MUSCULAR DYSTROPHY.Utrophin: An autosomally-encoded 376-kDa cytoskeletal protein that is similar in structure and function to DYSTROPHIN. It is a ubiquitously-expressed protein that plays a role in anchoring the CYTOSKELETON to the PLASMA MEMBRANE.

Processing of endogenous pre-mRNAs in association with SC-35 domains is gene specific. (1/1292)

Analysis of six endogenous pre-mRNAs demonstrates that localization at the periphery or within splicing factor-rich (SC-35) domains is not restricted to a few unusually abundant pre-mRNAs, but is apparently a more common paradigm of many protein-coding genes. Different genes are preferentially transcribed and their RNAs processed in different compartments relative to SC-35 domains. These differences do not simply correlate with the complexity, nuclear abundance, or position within overall nuclear space. The distribution of spliceosome assembly factor SC-35 did not simply mirror the distribution of individual pre-mRNAs, but rather suggested that individual domains contain both specific pre-mRNA(s) as well as excess splicing factors. This is consistent with a multifunctional compartment, to which some gene loci and their RNAs have access and others do not. Despite similar molar abundance in muscle fiber nuclei, nascent transcript "trees" of highly complex dystrophin RNA are cotranscriptionally spliced outside of SC-35 domains, whereas posttranscriptional "tracks" of more mature myosin heavy chain transcripts overlap domains. Further analyses supported that endogenous pre-mRNAs exhibit distinct structural organization that may reflect not only the expression and complexity of the gene, but also constraints of its chromosomal context and kinetics of its RNA metabolism.  (+info)

Hindlimb immobilization applied to 21-day-old mdx mice prevents the occurrence of muscle degeneration. (2/1292)

Dystrophin-deficient skeletal muscles of mdx mice undergo their first rounds of degeneration-regeneration at the age of 14-28 days. This feature is thought to result from an increase in motor activity at weaning. In this study, we hypothesize that if the muscle is prevented from contracting, it will avoid the degenerative changes that normally occur. For this purpose, we developed a procedure of mechanical hindlimb immobilization in 3-wk-old mice to restrain soleus (Sol) and extensor digitorum longus (EDL) muscles in the stretched or shortened position. After a 14-day period of immobilization, the striking feature was the low percentage of regenerated (centronucleated) myofibers in Sol and EDL muscles, regardless of the length at which they were fixed, compared with those on the contralateral side (stretched Sol: 8.4 +/- 6.5 vs. 46.6 +/- 10.3%, P = 0.0008; shortened Sol: 1.2 +/- 1.6 vs. 50.4 +/- 16.4%, P = 0.0008; stretched EDL: 05 +/- 0.5 vs. 32.9 +/- 17.5%, P = 0. 002; shortened EDL: 3.3 +/- 3.1 vs. 34.7 +/- 11.1%, P = 0.002). Total numbers of myofibers did not change with immobilization. This study shows that limb immobilization prevents the occurrence of the first round of myofiber necrosis in mdx mice and suggests that muscle contractions play a role in the skeletal muscle degeneration of dystrophin-deficient mdx mouse muscles.  (+info)

Increased calcium entry into dystrophin-deficient muscle fibres of MDX and ADR-MDX mice is reduced by ion channel blockers. (3/1292)

1. Single fibres were enzymatically isolated from interosseus muscles of dystrophic MDX mice, myotonic-dystrophic double mutant ADR-MDX mice and C57BL/10 controls. The fibres were kept in cell culture for up to 2 weeks for the study of Ca2+ homeostasis and sarcolemmal Ca2+ permeability. 2. Resting levels of intracellular free Ca2+, determined with the fluorescent Ca2+ indicator fura-2, were slightly higher in MDX (63 +/- 20 nM; means +/- s.d.; n = 454 analysed fibres) and ADR-MDX (65 +/- 12 nM; n = 87) fibres than in controls (51 +/- 20 nM; n = 265). 3. The amplitudes of electrically induced Ca2+ transients did not differ between MDX fibres and controls. Decay time constants of Ca2+ transients ranged between 10 and 55 ms in both genotypes. In 50 % of MDX fibres (n = 68), but in only 20 % of controls (n = 54), the decay time constants were > 35 ms. 4. Bath application of Mn2+ resulted in a progressive quench of fura-2 fluorescence emitted from the fibres. The quench rate was about 2 times higher in MDX fibres (3.98 +/- 1.9 % min-1; n = 275) than in controls (2.03 +/- 1.4 % min-1; n = 204). The quench rate in ADR-MDX fibres (2.49 +/- 1.4 % min-1; n = 87) was closer to that of controls. 5. The Mn2+ influx into MDX fibres was reduced to 10 % by Gd3+, to 19 % by La3+ and to 47 % by Ni2+ (all at 50 microM). Bath application of 50 microM amiloride inhibited the Mn2+ influx to 37 %. 6. We conclude that in isolated, resting MDX muscle fibres the membrane permeability for divalent cations is increased. The presumed additional influx of Ca2+ occurs through ion channels, but is well compensated for by effective cellular Ca2+ transport systems. The milder dystrophic phenotype of ADR-MDX mice is correlated with a smaller increase of their sarcolemmal Ca2+ permeability.  (+info)

Characterization of dystrophin and utrophin diversity in the mouse. (4/1292)

Utrophin is a 400 kDa autosomal homolog of dystrophin and a component of the submembranous cytoskeleton. While multiple dystrophin isoforms have been identified along with alternatively spliced products, to date only two different mRNA species of utrophin have been identified. To determine the degree of evolutionary conservation between dystrophin and utrophin isoforms, we have compared their expression patterns in adult mice. Northern blot analysis of multiple adult tissues confirmed that only two major sizes of transcripts are produced from each gene: 13 and 5.5 kb from utrophin and 14 and 4.8 kb from dystrophin. However, western blot analysis detected several putative short utrophin isoforms that may be homologs of the dystrophin isoforms Dp140, Dp116 and Dp71. We also identified an alternatively spliced utrophin transcript that lacks the equivalent of the alternatively spliced dystrophin exon 71. Finally, we demonstrated that the C-terminal domain of utrophin targeted to neuromuscular junctions in normal mice, but localized to the sarcolemma efficiently only in the absence of dystrophin. Our results provide further evidence for a common evolutionary origin of the utrophin and dystrophin genes.  (+info)

Ecto-ATPase activity of alpha-sarcoglycan (adhalin). (5/1292)

alpha-Sarcoglycan is a component of the sarcoglycan complex of dystrophin-associated proteins. Mutations of any of the sarcoglycan genes cause specific forms of muscular dystrophies, collectively termed sarcoglycanopathies. Importantly, a deficiency of any specific sarcoglycan affects the expression of the others. Thus, it appears that the lack of sarcoglycans deprives the muscle cell of an essential, yet unknown function. In the present study, we provide evidence for an ecto-ATPase activity of alpha-sarcoglycan. alpha-Sarcoglycan binds ATP in a Mg2+-dependent and Ca2+-independent manner. The binding is inhibited by 3'-O-(4-benzoyl)benzoyl ATP and ADP. Sequence analysis reveals the existence of a consensus site for nucleotide binding in the extracellular domain of the protein. An antibody against this sequence inhibits the binding of ATP. A dystrophin.dystrophin-associated protein preparation demonstrates a Mg-ATPase activity that is inhibited by the antibody but not by inhibitors of endo-ATPases. In addition, we demonstrate the presence in the sarcolemmal membrane of a P2X-type purinergic receptor. These data suggest that alpha-sarcoglycan may modulate the activity of P2X receptors by buffering the extracellular ATP concentration. The absence of alpha-sarcoglycan in sarcoglycanopathies leaves elevated the concentration of extracellular ATP and the persistent activation of P2X receptors, leading to intracellular Ca2+ overload and muscle fiber death.  (+info)

Characterization of the transmembrane molecular architecture of the dystroglycan complex in schwann cells. (6/1292)

We have demonstrated previously 1) that the dystroglycan complex, but not the sarcoglycan complex, is expressed in peripheral nerve, and 2) that alpha-dystroglycan is an extracellular laminin-2-binding protein anchored to beta-dystroglycan in the Schwann cell membrane. In the present study, we investigated the transmembrane molecular architecture of the dystroglycan complex in Schwann cells. The cytoplasmic domain of beta-dystroglycan was co-localized with Dp116, the Schwann cell-specific isoform of dystrophin, in the abaxonal Schwann cell cytoplasm adjacent to the outer membrane. beta-dystroglycan bound to Dp116 mainly via the 15 C-terminal amino acids of its cytoplasmic domain, but these amino acids were not solely responsible for the interaction of these two proteins. Interestingly, the beta-dystroglycan-precipitating antibody precipitated only a small fraction of alpha-dystroglycan and did not precipitate laminin and Dp116 from the peripheral nerve extracts. Our results indicate 1) that Dp116 is a component of the submembranous cytoskeletal system that anchors the dystroglycan complex in Schwann cells, and 2) that the dystroglycan complex in Schwann cells is fragile compared with that in striated muscle cells. We propose that this fragility may be attributable to the absence of the sarcoglycan complex in Schwann cells.  (+info)

Extensive but coordinated reorganization of the membrane skeleton in myofibers of dystrophic (mdx) mice. (7/1292)

We used immunofluorescence techniques and confocal imaging to study the organization of the membrane skeleton of skeletal muscle fibers of mdx mice, which lack dystrophin. beta-Spectrin is normally found at the sarcolemma in costameres, a rectilinear array of longitudinal strands and elements overlying Z and M lines. However, in the skeletal muscle of mdx mice, beta-spectrin tends to be absent from the sarcolemma over M lines and the longitudinal strands may be disrupted or missing. Other proteins of the membrane and associated cytoskeleton, including syntrophin, beta-dystroglycan, vinculin, and Na,K-ATPase are also concentrated in costameres, in control myofibers, and mdx muscle. They also distribute into the same altered sarcolemmal arrays that contain beta-spectrin. Utrophin, which is expressed in mdx muscle, also codistributes with beta-spectrin at the mutant sarcolemma. By contrast, the distribution of structural and intracellular membrane proteins, including alpha-actinin, the Ca-ATPase and dihydropyridine receptors, is not affected, even at sites close to the sarcolemma. Our results suggest that in myofibers of the mdx mouse, the membrane- associated cytoskeleton, but not the nearby myoplasm, undergoes widespread coordinated changes in organization. These changes may contribute to the fragility of the sarcolemma of dystrophic muscle.  (+info)

Membrane targeting and stabilization of sarcospan is mediated by the sarcoglycan subcomplex. (8/1292)

The dystrophin-glycoprotein complex (DGC) is a multisubunit complex that spans the muscle plasma membrane and forms a link between the F-actin cytoskeleton and the extracellular matrix. The proteins of the DGC are structurally organized into distinct subcomplexes, and genetic mutations in many individual components are manifested as muscular dystrophy. We recently identified a unique tetraspan-like dystrophin-associated protein, which we have named sarcospan (SPN) for its multiple sarcolemma spanning domains (Crosbie, R.H., J. Heighway, D.P. Venzke, J.C. Lee, and K.P. Campbell. 1997. J. Biol. Chem. 272:31221-31224). To probe molecular associations of SPN within the DGC, we investigated SPN expression in normal muscle as a baseline for comparison to SPN's expression in animal models of muscular dystrophy. We show that, in addition to its sarcolemma localization, SPN is enriched at the myotendinous junction (MTJ) and neuromuscular junction (NMJ), where it is a component of both the dystrophin- and utrophin-glycoprotein complexes. We demonstrate that SPN is preferentially associated with the sarcoglycan (SG) subcomplex, and this interaction is critical for stable localization of SPN to the sarcolemma, NMJ, and MTJ. Our experiments indicate that assembly of the SG subcomplex is a prerequisite for targeting SPN to the sarcolemma. In addition, the SG- SPN subcomplex functions to stabilize alpha-dystroglycan to the muscle plasma membrane. Taken together, our data provide important information about assembly and function of the SG-SPN subcomplex.  (+info)

  • Patterns of dystrophin and β-galactosidase expression were examined in mdx mice after i.m. injections of synthetic microspheres (MF-2) loaded with full-length (pHSADy) or mini-dystrophin gene (pSG5dys) cDNA plasmid constructs or with LacZ marker gene (pCMV-LacZ). (nature.com)
  • We report here for the first time efficient transfection of mdx mice myofibers with dystrophin gene constructs delivered in vivo by the microsphere particles MF-2. (nature.com)
  • The levels of dystrophin gene expression in different skeletal muscles as a function of time was examined in mdx mice after a single i.m. administration of microspheres loaded with 25 μg of full-length dystrophin cDNA (MF2/pHSADy). (nature.com)
  • Consistently, only minimum amount of dystrophin expression can be detected in the cardiac muscle even after repeated injections of both 2OMePS AON and PMO in all mdx mice aged 6 months or younger (Lu et al. (fitness-vip.com)
  • Because dysferlin and dystrophin play different roles in maintaining muscle cell integrity, we hypothesized that disrupting sarcolemmal integrity with dystrophin deficiency would exacerbate the pathology in dysferlin-null mice and allow further characterization of the role of dysferlin in skeletal muscle. (biomedcentral.com)
  • To test our hypothesis, we generated dystrophin/dysferlin double-knockout (DKO) mice by breeding mdx mice with dysferlin-null mice and analyzed the effects of a combined deficiency of dysferlin and dystrophin on muscle pathology and sarcolemmal integrity. (biomedcentral.com)
  • Dystrophin/dysferlin-deficient mice provide a very useful model with which to evaluate the effectiveness of therapies designed to treat dysferlin deficiency. (biomedcentral.com)
  • In DMD patients and mdx mice, which also have a mutation in the dystrophin gene, loss of dystrophin disrupts the link between the cytoskeleton and the ECM, leading to the loss of sarcolemmal integrity. (biomedcentral.com)
  • The treated mice show persistent production of dystrophin at normal levels in large numbers of muscle fibers and show functional improvement of the treated muscle. (qxmd.com)
  • At 90 days post-transplant, dystrophin expression in cardiac muscles of DEC injected mice significantly increased (15.73% ± 5.70 -MB wt /MB mdx and 5.22% ± 1.10 - MB wt /MSC mdx DEC) when compared to vehicle injected controls (2.01% ± 1.36) and, correlated with improved ejection fraction and fractional shortening on echocardiography. (springer.com)
  • Dystrophin is a complex plasmalemmal-cytoskeletal linker protein that possesses multiple functional domains, autosomal and X-linked homologs and associated binding proteins that form multiunit signaling complexes whose composition is unique to each cellular and developmental context. (elsevier.com)
  • In DMD/BMD, the individual profiles of cognitive and behavioral deficits, mental retardation and other phenotypic variations appear to depend on complex profiles of transcriptional regulation associated with individual dystrophin mutations that result in the corresponding presence or absence of individual brain dystrophin isoforms that normally exhibit developmental, regional and cell-type-specific expression and functional regulation. (elsevier.com)
  • Thus, splicing around mutations can generate a shortened but in-frame transcript, permitting translation of a partially functional dystrophin protein. (qxmd.com)
  • We previously reported functional improvements correlating with dystrophin restoration following transplantation of Dystrophin Expressing Chimeric Cells (DEC) of myoblast origin in the mdx and mdx/scid mouse models. (springer.com)
  • Eteplirsen is a morpholino antisense oligomer that triggers the excision of the out-of-frame exon 51 during the pre-mRNA splicing of the dystrophin RNA transcript, leading to the production of truncated, yet functional dystrophin. (biovox.eu)
  • Solid Biosciences is preparing an initial clinical trial for an AAV-based therapy that delivers a shortened, yet functional version of dystrophin) and gene editing therapy (e.g. (biovox.eu)
  • The key challenge with these ongoing approaches will be to impact a sufficiently high fraction of the muscle cells and to supply enough functional dystrophin to restore muscle function. (biovox.eu)
  • Therefore, connection of defined areas of plasma membrane or its constituents such as ion channels to single sarcomeres might be a potential function exerted by dystrophin alone or in conjunction with other submembrane cytoskeletal proteins. (rupress.org)
  • Through additional interactions with a variety of proteins of the extracellular matrix, plasma membrane, cytoskeleton and distinct intracellular compartments, brain dystrophin acquires the capability to participate in the modulatory actions of a large number of cellular signaling pathways. (elsevier.com)
  • Dystrophin is a vital structural link between the extracellular matrix and the cytoskeletal proteins and plays an essential role in several important biochemical extracellular signaling pathways. (springer.com)
  • In skeletal muscle, there are a few known PDZ-domain proteins, which include neuronal nitric oxide synthase and syntrophin, both of which are components of the dystrophin complex, and actinin-associated LIM protein, which binds to the spectrin-like repeats of alpha-actinin-2. (unipd.it)
  • Dystrophin links the cytoskeleton to the sarcolemma through direct interaction with β-dystroglycan. (biomedcentral.com)
  • Dystrophin plays an important role in linking the cytoskeleton to the sarcolemma through the direct interactions of its N-terminus with F-actin and its C-terminus with β-dystroglycan [ 2 ]. (biomedcentral.com)
  • Component of the dystrophin- associated glycoprotein complex which accumulates at the neuromuscular junction (NMJ) and at a variety of synapses in the peripheral and central nervous systems and has a structural function in stabilizing the sarcolemma. (bosterbio.com)
  • However, the rate of force recovery within 45 minutes following lengthening contractions was hampered in DKO muscles compared to mdx muscles or dysferlin-null muscles, suggesting that dysferlin is required for the initial recovery from lengthening contraction-induced muscle injury of the dystrophin-glycoprotein complex-compromised muscles. (biomedcentral.com)
  • Dystrophin is an integral component of the dystrophin-glycoprotein complex (DGC) and is localized to the inner surface of the plasma membrane [ 2 ]. (biomedcentral.com)
  • Direct visualization of the dystrophin network on skeletal muscle fiber membrane. (rupress.org)
  • We have shown that dystrophin molecules are not uniformly distributed over the humen, rat, and mouse skeletal muscle fiber surface using three independent methods. (rupress.org)
  • Incubation of single-teased muscle fibers with antibodies to dystrophin revealed a network of denser transversal rings (costameres) and finer longitudinal interconnections. (rupress.org)
  • Mechanical skinning of single-teased fibers revealed tighter mechanical connection of dystrophin to the plasma membrane than to the underlying internal domain of the muscle fiber. (rupress.org)
  • The entire dystrophin network remained preserved in its structure on isolated muscle sarcolemma and identical in appearance to the pattern observed on teased fibers. (rupress.org)
  • Dystrophin deficiency clinically manifests as skeletal and cardiac muscle weakness, leading to muscle wasting and premature death due to cardiac and respiratory failure. (springer.com)
  • PF-06939926 is an investigational gene transfer therapy intended to deliver its mini-dystrophin-encoding gene to muscle tissue for the targeted production of the micro-dystrophin protein. (medicalbiochemist.com)
  • AAV9.Muscle-promoter.micro-dystrophin). (medicalbiochemist.com)
  • AAV9.MuscleProtomter.mini-dystrophin (3.9Kb), The propriety muscle promoter drives the expression of the minidystrophin gene in the muscle tissue. (medicalbiochemist.com)
  • The Phase 1b study conducted to determine the safety and tolerability of the AAV9.Muscle-promoter.micro-dystrophin is completed and one year data is provided in the ASGCT Investor call. (medicalbiochemist.com)
  • The absence of any efficient pharmaceutical or biological (myoblast transplantation) methods for the treatment of DMD makes the development of gene therapy approaches for widespread systemic delivery of dystrophin gene to skeletal muscles very urgent for the correction and management of this primary lethal genetic disorder. (nature.com)
  • Out-of-frame mutations in DMD lead to absence of the dystrophin protein, while in-frame BMD mutations cause production of internally deleted dystrophin. (bmj.com)
  • Dystrophin deficiency in DMD/BMD patients and in the mdx mouse model appears to impair intracellular calcium homeostasis and to disrupt multiple protein-protein interactions that normally promote information transfer and signal integration from the extracellular environment to the nucleus within regulated microdomains. (elsevier.com)
  • Dystrophin deficiency unmasks the function of dysferlin in membrane repair during lengthening contractions. (biomedcentral.com)
  • MF-2/dystrophin cDNA par- ticles were detected by FISH analysis in about 60-70% of myofiber nuclei in muscles of injected and contralateral limbs 7 days after application. (nature.com)
  • The presence of human dystrophin cDNA and its products in all skeletal muscles and in different internal organs was proven by PCR and RT-PCR analysis. (nature.com)
  • 2006), whereas the same treatment can induce high levels of dystrophin in skeletal muscles. (fitness-vip.com)
  • However, direct injection of AON into cardiac muscles showed effective dystrophin induction, suggesting that lower delivery efficiency is perhaps the most critical factor (Vitiello et al. (fitness-vip.com)
  • Increasing experimental evidence suggests that in adult life, dystrophin normally modulates synaptic terminal integrity, distinct forms of synaptic plasticity and regional cellular signal integration. (elsevier.com)
  • Seven promoters scattered throughout the huge DMD/BMD gene locus normally code for distinct isoforms of the gene product, dystrophin, that exhibit nervous system developmental, regional and cell-type specificity. (elsevier.com)
  • 1, 2 Myofibers lacking dystrophin are abnormally susceptible to contraction-induced sarcolemma damage with subsequent myofiber dysfunction, necrosis and regeneration leading ultimately to the replacement of the lost fibers by adipose and connective tissue and premature death often associated with cardiomyopathy. (nature.com)
  • Dystrophin and its associated proteins form a scaffold underneath the cardiomyocyte membrane and connect the intracellular cytoskeleton to the extracellular matrix. (biomedsearch.com)
  • It shares features with other cytoskeletal proteins such as SPECTRIN and alpha-actinin but the precise function of dystrophin is not clear. (curehunter.com)
  • Videos accompanying the online publication show visual evidence of pronounced curving of the spine and dramatically reduced mobility as a result of deficiency of both dystrophin and utrophin proteins (Hyperlink to: Mouse Pretreatment/Supplementary Video S1, http://www.avibio.com/videos03.php ). (scienceblog.com)
  • A macromolecular complex of proteins that includes DYSTROPHIN and DYSTROPHIN-ASSOCIATED PROTEINS. (curehunter.com)
  • Dystrophin and its partially redundant homolog Utrophin are associated with a number of other proteins, members of the Dystrophin-glycoprotein complex (DGC) ( Ervasti and Campbell, 1991 ). (jneurosci.org)
  • Dystrophins and dystrobrevins are distantly related proteins with important but poorly understood roles in the function of metazoan muscular and neuronal tissues. (biomedcentral.com)
  • PURPOSE: To test the hypothesis that exercise training (ET) would alleviate age-related disruption of localization in DGC proteins (dystrophin, α-syntrophin, and β-sarcoglycan), and ET will upregulate decorin. (wku.edu)
  • Dystrophin localizes to the sarcolemma and stabilizes a complex of proteins (dystrophin-associated proteins, DAPs) that link the extracellular matrix to the actin cytoskeleton ( Ohlendieck, 1996 ). (biologists.org)
  • Several studies have shown that α-dystrobrevin can bind many of the same proteins that associate with dystrophin. (biologists.org)
  • an adapter protein that links signaling proteins to the dystrophin-dystrobrevin scaffold. (biologists.org)
  • Therefore, both dystrophin and dystrobrevin serve as scaffolds for a variety of signaling proteins. (biologists.org)
  • Dystrophin-less DMD and MDX myotubes were more susceptible to hypoosmotic shock than controls, as monitored by the uptake of external horseradish peroxidase and release of the soluble enzymes creatinine kinase or pyruvate kinase and of radiolabelled proteins. (biologists.org)
  • The present study was intended to identify all known members of the dystrophin superfamily and their associated proteins expressed in Müller glial cells (MGC). (arvojournals.org)
  • In morphologically preserved differentiated Müller cells, Dp71f was localized in clusters, utrophin was diffusely distributed in the cytoplasm, and dystrophin-associated proteins (DAPs) were membrane-bound. (arvojournals.org)
  • 1 In the muscle, dystrophin is a submembranous cytoskeletal protein 2 that links actin 3 to a complex of dystrophin-associated proteins (DAPs) composed of transmembranous and submembranous proteins, such as dystroglycans, sarcoglycans, and syntrophins. (arvojournals.org)
  • Utrophin and dystrophins are minor actin-binding proteins present in muscle and non-muscle cytoskeleton. (inserm.fr)
  • Two new dystrophin isoforms were found, Dp71f and Dp71 d, as well as the Up71 isoform and the dystrophin-associated proteins, alpha and beta -dystrobrevins. (inserm.fr)
  • Distribution of Dp71d/Dp71delta110m, Up400/Up71 and dystrophin-associated proteins in relation to the actin cytoskeleton was evaluated by confocal microscopy in both resting and platelets adhered on glass. (inserm.fr)
  • Therefore, connection of defined areas of plasma membrane or its constituents such as ion channels to single sarcomeres might be a potential function exerted by dystrophin alone or in conjunction with other submembrane cytoskeletal proteins. (rupress.org)
  • In skeletal muscle, dystrophin is associated with a large, oligomeric complex of proteins that includes dystroglycans, sarcoglycans, dystrobrevins, syntrophins and sarcospan ( Straub and Campbell 1997 ). (rupress.org)
  • Of the numerous elements necessary for proper functioning of this synaptic contact, dystrophin proteins in the eye play an important role. (arvojournals.org)
  • Dystrophin is a complex plasmalemmal-cytoskeletal linker protein that possesses multiple functional domains, autosomal and X-linked homologs and associated binding proteins that form multiunit signaling complexes whose composition is unique to each cellular and developmental context. (elsevier.com)
  • Through additional interactions with a variety of proteins of the extracellular matrix, plasma membrane, cytoskeleton and distinct intracellular compartments, brain dystrophin acquires the capability to participate in the modulatory actions of a large number of cellular signaling pathways. (elsevier.com)
  • Members of the dystrophin family of proteins perform a critical role in the maintenance of membrane-associated complexes at points of intercellular contact in vertebrate cells. (nih.gov)
  • Association of syncollin and desmin: Linking intermediate filament proteins to the dystrophin-associated protein complex. (ox.ac.uk)
  • A group of proteins including dystrophin bound together which form a critical link between the inside and outside of muscle cells. (musculardystrophyuk.org)
  • The absence of dystrophin leads to a dramatic reduction of the dystrophin-associated proteins (156DAG, 59DAP, 50DAG, 43DAG and 35DAG) in the sarcolemma of patients with Duchenne muscular dystrophy and mdx mice 2,6-8 . (umn.edu)
  • Here we demonstrate that dystrophin-related protein (DRP, utrophin), an autosomal homologue of dystrophin 9,17 , is associated with an identical or antigenically similar complex of sarcolemmal proteins and that DRP and the dystrophin/DRP-associated proteins colocalize to the neuromuscular junction in Duchenne muscular dystrophy and mdx muscle. (umn.edu)
  • The DRP and dystrophin/DRP-associated proteins are found throughout the sarcolemma in small-calibre skeletal muscles and cardiac muscle of adult mdx mice. (umn.edu)
  • The dystrophin-glycoprotein complex (DGC) comprises a group of proteins that are critical to the stability of muscle fiber membranes and to the linking of the actin cytoskeleton to the extracellular matrix. (wikipedia.org)
  • Dystrophin is a protein located between the sarcolemma and the outermost layer of myofilaments in the muscle fiber (myofiber). (wikipedia.org)
  • Component of the dystrophin-associated glycoprotein complex which accumulates at the neuromuscular junction (NMJ) and at a variety of synapses in the peripheral and central nervous systems and has a structural function in stabilizing the sarcolemma. (abcam.com)
  • 1, 2 Myofibers lacking dystrophin are abnormally susceptible to contraction-induced sarcolemma damage with subsequent myofiber dysfunction, necrosis and regeneration leading ultimately to the replacement of the lost fibers by adipose and connective tissue and premature death often associated with cardiomyopathy. (nature.com)
  • The absence of dystrophin at the sarcolemma also delocalizes and downregulates nitric oxide synthase (nNOS) and alters enzymatic antioxidant responses, leading to an increase in oxidative stress. (mdpi.com)
  • These results position archvillin (zeige SVIL Antikörper ) as a mechanically sensitive component of the dystrophin (zeige DMD Antikörper ) complex and demonstrate that signaling defects caused by loss of gamma-SG occur both at the sarcolemma and in the nucleus. (antikoerper-online.de)
  • Despite restoration of sarcolemmal α-syntrophin, neuronal nitric oxide synthase (nNOS) was not localized to the sarcolemma, suggesting that nNOS requires both dystrophin and α-syntrophin for correct localization. (biologists.org)
  • It is α-dystrobrevin-2a that is most abundant on the sarcolemma where it colocalizes with dystrophin. (biologists.org)
  • We have demonstrated gene therapy with this vector by restoring dystrophin expression in DMD myoblasts, where dystrophin was expressed at the sarcolemma of myotubes after myogenic differentiation. (physiciansweekly.com)
  • The entire dystrophin network remained preserved in its structure on isolated muscle sarcolemma and identical in appearance to the pattern observed on teased fibers. (rupress.org)
  • A population of γ-actin filaments was stably associated with sarcolemma isolated from normal muscle and displayed a costameric pattern that precisely overlapped with dystrophin. (rupress.org)
  • However, costameric actin was absent from all sarcolemma isolated from dystrophin-deficient mdx mouse muscle even though it was localized to costameres in situ. (rupress.org)
  • Our data demonstrate that the dystrophin complex forms a mechanically strong link between the sarcolemma and the costameric cytoskeleton through interaction with γ-actin filaments. (rupress.org)
  • Dystrophin labelling in equatorial regions of normal intrafusal fibers, however, showed dystrophin-deficient segments alternating in a spiral fashion with positive-staining domains along the sarcolemma. (ubc.ca)
  • Dystrophin links the cytoskeleton to the sarcolemma through direct interaction with β-dystroglycan. (biomedcentral.com)
  • Dystrophin plays an important role in linking the cytoskeleton to the sarcolemma through the direct interactions of its N-terminus with F-actin and its C-terminus with β-dystroglycan [ 2 ]. (biomedcentral.com)
  • Moreover, we hypothesize that dystrophin play a critical role in ventricular remodeling in ischemic myocardium and treatment targeting restoration of dystrophin onto membrane could benefit for ischemic cardiomyopathy. (biomedsearch.com)
  • The absence of dystrophin leads to myofiber membrane fragility that results in the progressive muscular degeneration that characterizes DMD ( Sussman, 2002 ). (frontiersin.org)
  • Most of the dystrophin protein consists of a central domain made of 24 spectrin-like coiled-coil repeats (R). Using small angle neutron scattering (SANS) and the contrast variation technique, we specifically probed the structure of the three first consecutive repeats 1-3 (R1-3), a part of dystrophin known to physiologically interact with membrane lipids. (cea.fr)
  • Dystrophin maintains the integrity of striated muscles by linking the actin cytoskeleton with the cell membrane. (jci.org)
  • The dystrophin-glycoprotein complex (DGC) is localized and integrated into the cell membrane. (wku.edu)
  • These results lend further support to the suggested stabilizing role of dystrophin in the context of the membrane-cytoskeletal complex. (biologists.org)
  • The results of this study suggest that dystrophin is not an integral part of the subsynaptic sensory-membrane in equatorial regions of normal intrafusal fibers, and, that the neurotrophic effect of sensory innervation is not the principle cause of this unique arrangement of dystrophin in equatorial regions. (ubc.ca)
  • Dystrophin is an integral component of the dystrophin-glycoprotein complex (DGC) and is localized to the inner surface of the plasma membrane [ 2 ]. (biomedcentral.com)
  • The following antibody was used in this experiment: Dystrophin Polyclonal Antibody from Thermo Fisher Scientific, catalog # 12715-1-AP. (thermofisher.com)
  • Cultures containing dystrophic myoblasts were seeded in 8 well chambers and were targeted with a 72 hour recovery time after the addition of the either the nonspecific ODN (A) or mdx47NT (B). These cells were then allowed to differentiate for 96 hours at which point they were fixed and incubated with antibody specific for a rabbit polyclonal antibody that recognizes dystrophin and a secondary Alexa fluor labeled antibody (red). (nih.gov)
  • The entire assay was performed in microscope chambers so that the samples could be probed directly with an antibody specific for the dystrophin protein. (nih.gov)
  • Transduction efficiency was assessed by immuno-staining using an antibody (Manex1a) that recognizes the N-terminus of micro-dystrophin. (biomedcentral.com)
  • Spindles were serially-sectioned in transverse and longitudinal planes, and they were double-labelled with an antibody to dystrophin and with a 200 kD neurofilament protein antibody which revealed their sensory innervation. (ubc.ca)
  • Mouse IgG monoclonal antibody for Dystrophin, dystrophin (DMD) detection. (bosterbio.com)
  • Results from a Phase 1 proof-of-concept trial showed that injection of the drug into the muscles of a series of boys with DMD successfully induced dystrophin production in a dose-responsive manner. (scienceblog.com)
  • MF-2/dystrophin cDNA par- ticles were detected by FISH analysis in about 60-70% of myofiber nuclei in muscles of injected and contralateral limbs 7 days after application. (nature.com)
  • However, direct injection of AON into cardiac muscles showed effective dystrophin induction, suggesting that lower delivery efficiency is perhaps the most critical factor (Vitiello et al. (fitness-vip.com)
  • 2008). This is further supported by the restoration of dystrophin in cardiac muscles via AAV-mediated AON delivery (Denti et al. (fitness-vip.com)
  • Immunoblotting of dystrophin in DMD muscles reveals the total absence of dystrophin except in some revertant fibers. (thefreedictionary.com)
  • The latter study showed that it is possible to correct the genetic error in the cells that no longer produce dystrophin protein, and inject corrected cells stimulating the regeneration of muscles. (stemcellsgroup.com)
  • It is caused by a mutation in the DMD gene that carries the instruction to make dystrophin, the protein that provides structural support and protection to the muscles. (musculardystrophynews.com)
  • Recent studies suggest that dystrophin may contain unique domains that can help the heart better cope with the stress generated during contraction. (pharmiweb.com)
  • In this study, the researchers found that equal parts enzyme and guide RNA-targeted at a specific part of the DMD gene-didn't bump up the production of dystrophin very much. (the-scientist.com)
  • However, when the patients were evaluated three months later, long-term production of dystrophin protein from the corrected DMD gene was not detected. (nationwidechildrens.org)
  • Genetic, biochemical and anatomical studies of dystrophin suggest that a number of distinct functions are subserved by its great structural diversity. (nih.gov)
  • Dystrophin abnormalities are thought to occur in 100% of patients with DMD/BMD, although genetic abnormalities may only be detected in up to 65% of cases. (thermofisher.com)
  • A novel stress syndrome was characterized in pigs and the causative genetic factor most likely resides within DMD that results in less dystrophin protein and cardiac abnormalities that can lead to death under stressful conditions. (biomedcentral.com)
  • The secret: an ordinary virus with all its natural genetic material removed to make room for the dystrophin gene which triggers production of the protein. (umich.edu)
  • In this study, we aim to knockdown myostatin by means of exon skipping, a technique which has been successfully applied to reframe the genetic defect of dystrophin gene in DMD patients. (springer.com)
  • The proteoglycan-dystrophin complex in genetic cardiomyopathie. (mysciencework.com)
  • The proteoglycan-dystrophin complex in genetic cardiomyopathies--lessons from three siblings with limb-girdle muscular dystrophy-2I (LGMD-2I). (mysciencework.com)
  • parallels the structural deficiencies observed in other cytolinker-deficient tissues, further demonstrating a close relationship between dystrophin and other cytolinkers. (rupress.org)
  • The dystrophin-deficient mdx mouse has historically been used as the primary model of DMD, although this mouse does not experience the severe, body-wide dystrophy that considerably shortens lifespan in humans. (scienceblog.com)
  • Double-labelling for dystrophin and neurofilament protein showed that these dystrophin-deficient sites were subjacent to the annulospiral sensory-nerve wrappings terminating on the intrafusal fibers. (ubc.ca)
  • A large and complex gene on the X chromosome encodes dystrophin. (nih.gov)
  • The capacity of AAV1, AAV6 or AAV8 to cross the vascular endothelial barrier carrying a micro-dystrophin cDNA was compared under identical conditions with delivery through a catheter placed in the femoral artery of the mdx mouse. (biomedcentral.com)
  • Subsequent clinical trials have shown that two different AON chemistries, either 2'- O -methyl phosphorothioate (2'OMePS)[ 12 ] or phosphorodiamidate morpholino oligomer (PMO)[ 13 ] targeting DMD exon 51 can restore local dystrophin synthesis in DMD patients with no to minimum side effect. (springer.com)
  • Stripping away genes normally found in the virus not only frees up enough space for a full-sized version of dystrophin, it also may make it possible to avoid triggering the body's immune system, according to Chamberlain. (umich.edu)
  • Furthermore, combination of myostatin and dystrophin AONs induced simultaneous skipping of both genes. (springer.com)
  • In this study, we will dissect the role(s) these domains play in the heart, and more importantly, we will develop next-generation micro-dystrophin genes to more effectively protect the heart. (pharmiweb.com)
  • The latest report Dystrophin (DMD) - Pipeline Review, H1 2018, outlays comprehensive information on the Dystrophin (DMD) targeted therapeutics, complete with analysis by indications, stage of development, mechanism of action (MoA), route of administration (RoA) and molecule type. (marketresearch.com)
  • Independently, we will also request a meeting with the Agency to discuss the micro-dystrophin program with the goal of commencing a pivotal trial by year-end 2018. (firstwordpharma.com)
  • We have analyzed DNA from 72 Moroccan patients with DMD/BMD using the multiplex polymerase chain reaction (PCR) to screen for exon deletions within the dystrophin gene, and to estimate the frequency of these abnormalities. (hindawi.com)
  • Formation of two dystrophin-associated protein complexes (Dp71d/Dp71delta110m approximately DAPC and Up400/Up71 approximately DAPC) was demonstrated by co-immunoprecipitation and their distribution in relation to the actin cytoskeleton was characterised during platelet adhesion. (inserm.fr)