UMLS:C0026850 - FACTA Search

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Query: UMLS:C0026850 (muscular dystrophy)
5,870 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In skeletal muscle, the localization of nNOS is destabilized in the absence of dystrophin, which impacts muscle function and satellite cell activation. In neurons, the adaptor protein, carboxy-terminal PDZ ligand of nNOS (CAPON), regulates the distribution of neuronal nitric oxide synthase (nNOS), which produces the key signaling molecule nitric oxide (NO). While a CAPON-like gene is known to compensate functionally for a dystrophic phenotype in muscle of Caenorhabditis elegans, CAPON expression has not been reported for mammalian muscle. Here, CAPON expression was identified in mouse muscle using Northern and Western blotting and in situ hybridization in combination with immunostaining for laminin. CAPON RNA was expressed in developing normal and dystrophic muscles near fiber junctions with tendons, and levels increased from 1 to 3 weeks. In regenerating normal muscle and also in dystrophic muscles in the mdx mouse, CAPON transcripts were prominent in satellite cells and new myotubes. Expression of CAPON RNA increased in diaphragm muscle of normal and mdx mice after treatment with L-arginine, the NOS substrate. Both CAPON and utrophin protein levels increased in dystrophic quadriceps muscle after treatment with the steroid deflazacort plus L-arginine, known to reduce the dystrophic phenotype. The identification of CAPON transcripts and protein in mammalian muscle and responses to L-arginine suggest CAPON may have a functional role in stabilizing neuronal NOS in skeletal muscle in the cytoskeletal complex associated with dystrophin/utrophin, with possible applications to therapy for human muscular dystrophy.
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PMID:CAPON expression in skeletal muscle is regulated by position, repair, NOS activity, and dystrophy. 1556 Oct 99

In both forms of muscular dystrophy, the severe Duchenne's muscular dystrophy (DMD) with lifespan shortened to about 20 years and the milder Becker dystrophy (BDM) with normal lifespan, the gene defect is located at chromosome locus Xp21. The location is the same in the experimental model of DMD in the mdx mice. As the result of the gene defect a protein called dystrophin is either not synthesized, or is produced in traces. Although the structure of this protein is rather well established there are still many controversies about the dystrophin function. The most accepted suggestion supposes that it stabilizes sarcolemma in the course of the contraction-relaxation cycle. Solving the problem of dystrophin function is a prerequisite for introduction of an effective therapy. Among the different factors which might be responsible for the appearance and progress of dystrophic changes in muscles there is an excessive action of oxidative stress. In this review data indicating the influence of oxidative stress on the severity of the pathologic processes in dystrophy are discussed. Several pieces of data indicating the action of oxidative damage to different macromolecules in DMD/BDM are presented. Special attention is devoted to the degree of oxidative damage to muscle proteins, the activity of neuronal nitric oxide synthase (nNOS) and their involvement in defining the severity of the dystrophic processes. It is indicated that the severity of the morbid process is related to the degree of oxidative damage to muscle proteins and the decrease of the nNOS activity in muscles. Estimation of the degree of the destructive action of oxidative stress in muscular dystrophy may be a useful marker facilitating introduction of an effective antioxidant therapy and regulation of nNOS activity.
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PMID:The involvement of oxidative stress in determining the severity and progress of pathological processes in dystrophin-deficient muscles. 1599 Sep 24

C-terminal-truncated (DeltaC) microdystrophin is being developed for Duchenne muscular dystrophy gene therapy. Encouraging results have been achieved in the mdx mouse model. Unfortunately, mdx mice do not display the same phenotype as human patients. Evaluating DeltaC microdystrophin in a symptomatic model will be of significant relevance to human trials. Utrophin/dystrophin double-knockout (u-dko) mice were developed to model severe dystrophic changes in human patients. In this study we evaluated the therapeutic effect of the DeltaR4-R23/DeltaC microdystrophin gene (DeltaR4/DeltaC) after serotype-6 adeno-associated virus-mediated gene transfer in neonatal u-dko muscle. At 2 months after gene transfer, the percentage of centrally nucleated myofiber was reduced from 89.2 to 3.4% and muscle weight was normalized. Furthermore, we have demonstrated for the first time that DeltaC microdystrophin can eliminate interstitial fibrosis and macrophage infiltration and restore dystrobrevin and syntrophin to the dystrophin-associated glycoprotein complex. Interestingly neuronal nitric oxide synthase was not restored. The most impressive results were achieved in muscle force measurement. Neonatal gene therapy increased twitch- and tetanic-specific force. It also brought the response to eccentric contraction-induced injury to the normal range. In summary, our results suggest that the DeltaR4/DeltaC microgene holds great promise in preventing muscular dystrophy.
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PMID:C-terminal-truncated microdystrophin recruits dystrobrevin and syntrophin to the dystrophin-associated glycoprotein complex and reduces muscular dystrophy in symptomatic utrophin/dystrophin double-knockout mice. 1656 74

Duchenne muscular dystrophy is a severe disorder caused by mutations in the dystrophin gene. Dystrophin is required for assembly of the dystrophin-glycoprotein complex and provides a mechanically strong link between the cytoskeleton and the extracellular matrix. Several proteins in the complex also participate in signaling cascades, but the relationship between these signaling and mechanical functions in the development of muscular dystrophy is unclear. To explore the mechanisms of myofiber necrosis in dystrophin-deficient muscle, we tested the hypothesis that restoration of this complex without a link to the cytoskeleton ameliorates dystrophic pathology. Transgenic mice were generated that express Dp116, a non-muscle isoform of dystrophin that assembles the dystrophin-glycoprotein complex, in muscles of dystrophin-deficient mdx(4cv) mice. However, the phenotype of these mice was more severe than in controls. Displacement of utrophin by Dp116 correlated with the severity of dystrophy in different muscle groups. Comparison with other transgenic lines demonstrated that parts of the dystrophin central rod domain were required to localize neuronal nitric oxide synthase to the sarcolemma, but this was not correlated with presence or extent of dystrophy. Our results suggest that mechanical destabilization, rather than signaling dysfunction, is the primary cause of myofiber necrosis in dystrophin-deficient muscle.
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PMID:Dissecting the signaling and mechanical functions of the dystrophin-glycoprotein complex. 1656 68

Previous studies showed that nitricoxide synthase (NOS) and oxidative stress can induce skeletal muscle atrophy in the muscular dystrophy and inclusion-body myopathy. There is a correlation between NOS and oxidative stress. However, it is not clear, whether there are some changes of the NOS activity in prolonged alcoholic myopathy (PAM), and whether NOS activity has relation to amyotrophy of PAM. We established experimental alcoholic myopathy model of rats by prolonged alcohol intake. We found that there is a reduction in GSH-px (P < 0.05) and an increase of SOD (P < 0.05), MDA (P < 0.05) and iNOS (P < 0.05) in the plantaris of the experimental group by spectrophotometer. In the soleus of the experimental group, except for MDA showed an increase (P < 0.05), the other enzymes showed no obvious difference (P > 0.05). The immunohistochemistry results showed that there was obvious expression of iNOS in the cytoplasm of plantaris in the experimental group and there was no expression of iNOS in the control group. There was a decrease of nNOS expression on the membranes of the plantaris cells in the experimental group by immunofluorescence. Meanwhile, we found the expression of nNOS in some cytoplasm. Our results suggested that NOS might be an important factor during the development of PAM. We could infer that there are some disturbances with regard to output and scavenging of free radical in PAM. Alcohol can induce the oxidative stress reaction and further result in imbalance of the oxidant-antioxidant status in the organism.
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PMID:Nitricoxide synthase-induced oxidative stress in prolonged alcoholic myopathies of rats. 1760 8

alpha-Dystrobrevin associates with and is a homologue of dystrophin, the protein linked to Duchenne and Becker muscular dystrophies. We used a transgenic approach to restore alpha-dystrobrevin to the sarcolemma in mice that lack dystrophin (mdx mice) to study two interrelated functions: (1) the ability of alpha-dystrobrevin to rescue components of the dystrophin complex in the absence of dystrophin and (2) the ability of sarcolemmal alpha-dystrobrevin to ameliorate the dystrophic phenotype. We generated transgenic mice expressing alpha-dystrobrevin-2a linked to a palmitoylation signal sequence and bred them onto the alpha-dystrobrevin-null and mdx backgrounds. Expression of palmitoylated alpha-dystrobrevin prevented the muscular dystrophy observed in the alpha-dystrobrevin-null mice, demonstrating that the altered form of alpha-dystrobrevin was functional. On the mdx background, the palmitoylated form of alpha-dystrobrevin was expressed on the sarcolemma but did not significantly ameliorate the muscular dystrophy phenotype. Palmitoylated dystrobrevin restored alpha-syntrophin and aquaporin-4 (AQP4) to the mdx sarcolemma but was unable to recruit beta-dystroglycan or the sarcoglycans. Despite restoration of sarcolemmal alpha-syntrophin, neuronal nitric oxide synthase (nNOS) was not localized to the sarcolemma, suggesting that nNOS requires both dystrophin and alpha-syntrophin for correct localization. Thus, although nNOS and AQP4 both require interaction with the PDZ domain of alpha-syntrophin for sarcolemmal association, their localization is regulated differentially.
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PMID:Differential targeting of nNOS and AQP4 to dystrophin-deficient sarcolemma by membrane-directed alpha-dystrobrevin. 1805 22

Skeletal muscle nNOSmu (neuronal nitric oxide synthase mu) localizes to the sarcolemma through interaction with the dystrophin-associated glycoprotein (DAG) complex, where it synthesizes nitric oxide (NO). Disruption of the DAG complex occurs in dystrophinopathies and sarcoglycanopathies, two genetically distinct classes of muscular dystrophy characterized by progressive loss of muscle mass, muscle weakness and increased fatigability. DAG complex instability leads to mislocalization and downregulation of nNOSmu; but this is thought to play a minor role in disease pathogenesis. This view persists without knowledge of the role of nNOS in skeletal muscle contractile function in vivo and has influenced gene therapy approaches to dystrophinopathy, the majority of which do not restore sarcolemmal nNOSmu. We address this knowledge gap by evaluating skeletal muscle function in nNOS knockout (KN1) mice using an in situ approach, in which the muscle is maintained in its normal physiological environment. nNOS-deficiency caused reductions in skeletal muscle bulk and maximum tetanic force production in male mice only. Furthermore, nNOS-deficient muscles from both male and female mice exhibited increased susceptibility to contraction-induced fatigue. These data suggest that aberrant nNOSmu signaling can negatively impact three important clinical features of dystrophinopathies and sarcoglycanopathies: maintenance of muscle bulk, force generation and fatigability. Our study suggests that restoration of sarcolemmal nNOSmu expression in dystrophic muscles may be more important than previously appreciated and that it should be a feature of any fully effective gene therapy-based intervention.
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PMID:Functional deficits in nNOSmu-deficient skeletal muscle: myopathy in nNOS knockout mice. 1885 86

The disintegration of the dystrophin-glycoprotein complex represents the initial pathobiochemical insult in Duchenne muscular dystrophy. However, secondary changes in signalling, energy metabolism and ion homeostasis are probably the main factors that eventually cause progressive muscle wasting. Thus, for the proper evaluation of novel therapeutic approaches, it is essential to analyse the reversal of both primary and secondary abnormalities in treated muscles. Antisense oligomer-mediated exon skipping promises functional restoration of the primary deficiency in dystrophin. In this study, an established phosphorodiamidate morpholino oligomer coupled to a cell-penetrating peptide was employed for the specific removal of exon 23 in the mutated mouse dystrophin gene transcript. Using DIGE analysis, we could show the reversal of secondary pathobiochemical abnormalities in the dystrophic diaphragm following exon-23 skipping. In analogy to the restoration of dystrophin, beta-dystroglycan and neuronal nitric oxide synthase, the muscular dystrophy-associated differential expression of calsequestrin, adenylate kinase, aldolase, mitochondrial creatine kinase and cvHsp was reversed in treated muscle fibres. Hence, the re-establishment of Dp427 coded by the transcript missing exon 23 has counter-acted dystrophic alterations in Ca2+-handling, nucleotide metabolism, bioenergetic pathways and cellular stress response. This clearly establishes the exon-skipping approach as a realistic treatment strategy for diminishing diverse downstream alterations in dystrophinopathy.
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PMID:Proteomic profiling of antisense-induced exon skipping reveals reversal of pathobiochemical abnormalities in dystrophic mdx diaphragm. 1913 84

Reduction of neuronal nitric oxide synthase (nNOS) has been associated with the pathogenesis and clinical expression of inherited myopathies. To determine whether a defect in nNOS might be an adverse modulating factor in the course of limb-girdle muscular dystrophy, we investigated cytosolic and sarcolemmal nNOS expression in muscle biopsies from 32 patients with 7 forms of limb-girdle muscular dystrophy. Primary calpainopathy, dysferlinopathy, and caveolinopathy biopsies showed normal levels of cytosolic nNOS and preserved sarcolemmal nNOS immunoreactivity. By contrast, the cytosolic nNOS levels in sarcoglycanopathy muscles were variably reduced. Sarcolemmal nNOS immunoreactivity varied from absent to reduced, depending on the integrity of the sarcoglycan complex. In muscles with loss of the entire sarcoglycan complex, sarcolemmal nNOS was absent; it otherwise depended on the specific sarcoglycan gene and type of mutation. The integrity of the entire sarcoglycan complex is, therefore, essential for the stabilization of nNOS to the sarcolemma. Absence of sarcolemmal nNOS in sarcoglycanopathy muscle was always associated with severe muscular dystrophy and sometimes with dilated cardiomyopathy, supporting the hypothesis that nNOS defect might contribute to skeletal and cardiac muscle disease progression. These results emphasize the value of nNOS immunohistochemical analysis in limb-girdle muscular dystrophy and provide additional insights for future therapeutic interventions in these disorders.
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PMID:Sarcolemmal neuronal nitric oxide synthase defect in limb-girdle muscular dystrophy: an adverse modulating factor in the disease course? 1928 13

Progressive x-linked muscular dystrophy represents the most commonly inherited neuromuscular disorder in humans. Although the disintegration of the dystrophin-associated glycoprotein complex triggers the initial pathogenesis of Duchenne muscular dystrophy, secondary alterations in metabolic pathways, cellular signaling and the regulation of ion homeostasis are probably crucial factors that cause end-stage fibre degeneration. The application of mass spectrometry-based proteomics for the global cataloguing of muscle biomarkers has recently been applied to the analysis of the mdx animal model of muscular dystrophy and the biochemical evaluation of experimental exon skipping therapy. The fluorescence difference in-gel electrophoretic analysis of normal versus mdx diaphragm muscle revealed changed expression levels of proteins involved in nucleotide metabolism, Ca 2+-handling, the cellular stress response and key bioenergetic processes. The swift up-regulation of small heat shock proteins, such as cvHsp, seems to form an integral part of the repair mechanisms in dystrophic fibres and may be exploitable as a new option to treat inherited muscle degeneration. Importantly, the mass spectrometry-based profiling of mdx muscle following the specific removal of exon 23 in the mutated dystrophin gene transcript showed a partial reversal of important secondary changes. Experimental exon skipping restored the expression of the dystrophin isoform Dp427, its associated glycoprotein beta-dystroglycan, neuronal nitric oxide synthase, calsequestrin, adenylate kinase and the muscle-specific stress protein cvHsp. In the future, a well defined set of signature molecules could be used to improve diagnosis, monitor disease progression, identify new therapeutic pathways, and validate the effects of novel drugs or experimental treatments such as gene therapy.
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PMID:Proteomic profiling of x-linked muscular dystrophy. 2008 21

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