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

Muscle fibers attach to laminin in the basal lamina using two distinct mechanisms: the dystrophin glycoprotein complex and the alpha 7 beta 1 integrin. Defects in these linkage systems result in Duchenne muscular dystrophy (DMD), alpha 2 laminin congenital muscular dystrophy, sarcoglycan-related muscular dystrophy, and alpha 7 integrin congenital muscular dystrophy. Therefore, the molecular continuity between the extracellular matrix and cell cytoskeleton is essential for the structural and functional integrity of skeletal muscle. To test whether the alpha 7 beta 1 integrin can compensate for the absence of dystrophin, we expressed the rat alpha 7 chain in mdx/utr(-/-) mice that lack both dystrophin and utrophin. These mice develop a severe muscular dystrophy highly akin to that in DMD, and they also die prematurely. Using the muscle creatine kinase promoter, expression of the alpha 7BX2 integrin chain was increased 2.0-2.3-fold in mdx/utr(-/-) mice. Concomitant with the increase in the alpha 7 chain, its heterodimeric partner, beta 1D, was also increased in the transgenic animals. Transgenic expression of the alpha 7BX2 chain in the mdx/utr(-/-) mice extended their longevity by threefold, reduced kyphosis and the development of muscle disease, and maintained mobility and the structure of the neuromuscular junction. Thus, bolstering alpha 7 beta 1 integrin-mediated association of muscle cells with the extracellular matrix alleviates many of the symptoms of disease observed in mdx/utr(-/-) mice and compensates for the absence of the dystrophin- and utrophin-mediated linkage systems. This suggests that enhanced expression of the alpha 7 beta 1 integrin may provide a novel approach to treat DMD and other muscle diseases that arise due to defects in the dystrophin glycoprotein complex. A video that contrasts kyphosis, gait, joint contractures, and mobility in mdx/utr(-/-) and alpha 7BX2-mdx/utr(-/-) mice can be accessed at http://www.jcb.org/cgi/content/full/152/6/1207.
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PMID:Enhanced expression of the alpha 7 beta 1 integrin reduces muscular dystrophy and restores viability in dystrophic mice. 1125 21

Dystrophin links the actin cytoskeleton to the dystroglycan complex in the plasma membrane as part of the linkage between the cytoskeleton and the extracellular matrix. Damage to or absence of dystrophin causes Duchenne or Becker muscular dystrophy. It has been proposed that elevating the levels of utrophin, a close homologue of dystrophin, may act as a therapy for these forms of muscular dystrophy. This requires that there is a close functional equivalence of these two proteins. In both utrophin and dystrophin, the main actin-binding region is at the N terminus. It is related to sequences found in a number of other proteins including alpha-actinin, spectrin and fimbrin. Recent structural and biochemical studies of these proteins have shown that although the method of binding to actin is broadly similar, there are significant differences. There are even differences between utrophin and dystrophin. These studies imply that some caution should be applied to claims that utrophin and dystrophin are completely functionally interchangeable. In this paper, I review studies that elucidate and compare the actin-binding function of utrophin and dystrophin, particularly those initiated in the laboratory of Dr. John Kendrick-Jones at the MRC in Cambridge.
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PMID:Structural comparison of actin binding in utrophin and dystrophin. 1138 92

Duchenne's muscular dystrophy (DMD) is a fatal disease caused by mutations in the DMD gene that lead to quantitative and qualitative disturbances in dystrophin expression. Dystrophin is a member of the spectrin superfamily of proteins. Dystrophin itself is closely related to three proteins that constitute a family of dystrophin-related proteins (DRPs): the chromosome 6-encoded DRP or utrophin, the chromosome-X encoded, DRP2 and the chromosome-18 encoded, dystrobrevin. These proteins share sequence similarity and functional motifs with dystrophin. Current attempts at somatic gene therapy of DMD face numerous technical problems. An alternative strategy for DMD therapy, that circumvents many of these problems, has arisen from the demonstration that the DRP utrophin can functionally substitute for the missing dystrophin and its overexpression can rescue dystrophin-deficient muscle. Currently, a promising avenue of research consists of identifying molecules that would increase the expression of utrophin and the delivery of these molecules to dystrophin-deficient tissues as a means of DMD therapy. In this review, we will focus on DRPs from the perspective of strategies and issues related to upregulating utrophin expression for DMD therapy. Additionally, we will address the techniques used for anatomical, biochemical and physiological evaluation of the potential benefits of this and other forms of DMD therapy in dystrophin-deficient animal models.
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PMID:Harnessing the potential of dystrophin-related proteins for ameliorating Duchenne's muscular dystrophy. 1141 48

Muscular dystrophy is a nosology for a group of hereditary muscle disorders characterized by progressive wasting and weakness of skeletal muscle, where degeneration of muscle fibers is detected by pathological examination. Since the causative gene of Duchenne muscular dystrophy (DMD), the most severe and abundant form of muscular dystrophy, the DMD gene, and its product dystrophin was isolated by positional cloning by Dr. Kunkel and his colleagues, the studies on molecular pathologies of muscular dystrophy has been extensively developed. The current therapeutic approaches of muscular dystrophy, such as DMD involves pharmacological suppression of the inflammatory and immure responses, which usually provides only modest and temporary beneficial effects. Future approaches depend on cell and gene therapy technology and will require different strategies, none of which are currently ready to enter clinical practice. These approaches involve the efficient, non-antigenic gene transfer for in vivo gene therapy, pharmacological upregulation of the synthesis of utrophin, a related protein that compensates for the loss of dystrophin, and myogenic stem cell transplantation. These approaches could be integrated each other and called as molecular therapy.
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PMID:[Molecular therapy of muscular dystrophy]. 1146 75

X chromosome-linked muscular dystrophic mdx mouse lacks the sarcolemmal protein dystrophin and represents a genetic homologue of human Duchenne muscular dystrophy (DMD). The present study analysed some aspects of pathological processes such as fibrosis, frequency of centralized nuclei, presence of degenerative or regenerative fibres, expression of utrophin and associated protein complexes, and myosin heavy chain isoforms in three muscles [diaphragm (DIA), gastrocnemius (GTC) and masseter (MAS)] from old male mdx mice. All parameters investigated comparatively in these pathological muscles provided evidence that the MAS mdx muscle presents a slight deterioration pattern in comparison to that of DIA and GTC muscles. Utrophin and associated proteins are present in many cell clusters with continuous membrane labelling in MAS muscle. Respective proportions of myosin heavy chain isoforms, measured by electrophoresis/densitometry, showed only slight change in GTC muscle, significant evolution in DIA muscle but drastic isoform conversions in MAS muscle. These results highlighted the difference in deterioration susceptibility of various muscles to muscular dystrophy. The reason why this occurs in MAS muscles is still obscure and discussed in terms of the comparative developmental origins of these muscles.
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PMID:Comparative evolution of muscular dystrophy in diaphragm, gastrocnemius and masseter muscles from old male mdx mice. 1151 36

To optimize and evaluate treatments for muscular dystrophy, it is important to know the natural history of the disease in the absence of therapeutic intervention. Here we characterized disease progression of three mutant mouse strains of muscular dystrophy: mdx mice, which lack dystrophin; mdx:utrn-/- mice, which also lack utrophin; and dy/dy mice, which are deficient in laminin alpha2. Normal mice show a marked increase in forelimb strength over the first 10 weeks of life and little fatigue (<5%) over five consecutive strength trials. Mdx and mdx:utrn-/- mice demonstrate less strength then normal mice and approximately 40% fatigue at each age. Mdx mice become obese but mdx:utrn-/- mice do not. Dy/dy mice remain small and are much weaker than mdx and mdx:utrn-/- mice at all ages even when normalized to weight; however, they show only minimal fatigue (10%). This work demonstrates a distinct pattern of disease progression in each model and provides a foundation for assessing strategies for improving strength in each model.
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PMID:Three mouse models of muscular dystrophy: the natural history of strength and fatigue in dystrophin-, dystrophin/utrophin-, and laminin alpha2-deficient mice. 1211 88

Since the identification in 1987 of the gene for Duchenne muscular dystrophy (DMD), research on the molecular pathogenesis of muscular dystrophy has progressed extensively. In particular, discovery of the DMD gene product, dystrophin, led to the identification of dystrophin-associated proteins and, subsequently, the recognition of other types of muscular dystrophy caused by the defects in each of the sarcoglycan genes. On the other hand, effective therapy for DMD has not yet been established. Some of the viral vectors, such as adeno-associated virus vectors or lentiviral vector, have been proven to enable the long-term expression of the exogenous gene without overt host immune reactions. However, dystrophin cDNAs are too large (14kb) to be accommodated in these viral vectors. To solve this problem, we and other research groups succeeded in truncating full-length dystrophin cDNA to small dystrophin cDNA (4 to 5kb), the products of which protect dystrophin-deficient mdx muscle from contraction-induced membrane damage when introduced by viral vectors or as a transgene into mdx mice. The usefulness of these truncated dystrophin cDNAs should be confirmed using other animal models such as dystrophic dogs. To develop successful treatment of DMD, the authors believe that several different approaches should be used, such as cell transfer therapy, drug design to up-regulate utrophin, or a strategy to repair the mutation in vivo.
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PMID:Gene therapy for muscular dystrophies: current status and future prospects. 1160 45

The utrophin gene codes for a large cytoskeletal protein closely related to dystrophin, the gene mutated in Duchenne's muscular dystrophy. Although utrophin could functionally substitute for dystrophin, in Duchenne's muscular dystrophy patients it did not compensate for the absence of dystrophin because in adult muscle utrophin was poorly expressed and limited to subsynaptic nuclei. However, increased levels of utrophin have been observed in regenerated muscles fibers suggesting that utrophin up-regulation in muscle is feasible. We observed that utrophin mRNA was transiently up-regulated at early time points after muscle injury with a peak already 24 h after muscle damage and utrophin induction in activated satellite cells before fusion into young regenerated fibers. Injection of utrophin lacZ constructs into regenerating muscle demonstrated that the utrophin upstream promoter under the control of its intronic enhancer activated the transcription that leads to the expression of the reporter gene in the newly formed fibers, which was not limited to neuromuscular junctions. Utrophin enhancer activity was dependent on an AP-1 site, and in satellite cells of regenerating muscle the AP-1 factors Fra1, Fra2, and JunD were strongly induced. These results establish that utrophin was induced in adult muscle independently from neuromuscular junctions and suggest that growth factors and cytokines that mediate the muscle repair up-regulate utrophin transcription.
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PMID:The utrophin gene is transcriptionally up-regulated in regenerating muscle. 1187 58

The X-linked muscle-wasting disease Duchenne muscular dystrophy is caused by mutations in the gene encoding dystrophin. There is currently no effective treatment for the disease; however, the complex molecular pathology of this disorder is now being unravelled. Dystrophin is located at the muscle sarcolemma in a membrane-spanning protein complex that connects the cytoskeleton to the basal lamina. Mutations in many components of the dystrophin protein complex cause other forms of autosomally inherited muscular dystrophy, indicating the importance of this complex in normal muscle function. Although the precise function of dystrophin is unknown, the lack of protein causes membrane destabilization and the activation of multiple pathophysiological processes, many of which converge on alterations in intracellular calcium handling. Dystrophin is also the prototype of a family of dystrophin-related proteins, many of which are found in muscle. This family includes utrophin and alpha-dystrobrevin, which are involved in the maintenance of the neuromuscular junction architecture and in muscle homeostasis. New insights into the pathophysiology of dystrophic muscle, the identification of compensating proteins, and the discovery of new binding partners are paving the way for novel therapeutic strategies to treat this fatal muscle disease. This review discusses the role of the dystrophin complex and protein family in muscle and describes the physiological processes that are affected in Duchenne muscular dystrophy.
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PMID:Function and genetics of dystrophin and dystrophin-related proteins in muscle. 1191 91

Duchenne muscular dystrophy (DMD) is a congenital X-linked myopathy caused by lack of dystrophin protein expression. In DMD, the expression of many dystrophin-associated proteins (DAPs) is reduced along the sarcolemmal membrane, but the same proteins remain concentrated at the neuromuscular junction where utrophin, a dystrophin homologue, is expressed [Matsumura, K., Ervasti, J. M., Ohlendieck, K., Kahl, K. D. & Campbell, K. (1992) Nature (London) 360, 588-591]. This outcome has led to the concept that ectopic expression of a "synaptic scaffold" of DAPs and utrophin along myofibers might compensate for the molecular defects in DMD. Here we show that transgenic overexpression of the synaptic CT GalNAc transferase in the skeletal muscles of mdx animals (mdx/CT) increases the expression of utrophin and many DAPs, including dystroglycans, sarcoglycans, and dystrobrevins, along myofibers. Protein expression of utrophin and DAPs was equal to or above that of wild-type mice. In addition, alpha-dystroglycan was glycosylated with the CT carbohydrate antigen in mdx/CT but not in mdx muscles. mdx/CT mice have little or no evidence of muscular dystrophy by several standard measures; Serum creatine kinase levels, percentage of centrally located myofiber nuclei, and variance in myofiber diameter in mdx/CT muscles were dramatically reduced compared with mdx mice. These data suggest that ectopic expression of the CT GalNAc transferase creates a functional dystrophin-related complex along myofibers in the absence of dystrophin and should be considered as a target for therapeutic intervention in DMD.
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PMID:Overexpression of the cytotoxic T cell GalNAc transferase in skeletal muscle inhibits muscular dystrophy in mdx mice. 1196 16


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