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

The immunohistological localization of chondroitin sulfate (CS) has been studied in normal and pathological human muscle. The bovine nasal cartilage proteoglycan digested with chondroitinase ABC (BNC-PG-Ch ABC) has been utilized for the production of a rabbit polyclonal antiserum. In vitro studies showed that the antiserum binds to the unsaturated disaccharide that remains attached to the core protein after digestion of the CS chains with chondroitinase ABC (Ch ABC). As the disaccharide is created specifically by Ch ABC digestion of the CS chains, the antiserum allows the immunolocalization of CS on tissue sections digested with Ch ABC. The immunohistochemical study on normal and pathological muscle demonstrated a localization of CS in all the extracellular structures: endomysium, perimysium, muscle spindle capsule and intrafusal space. In pathological conditions, the CS was raised in all the cases with increased connective tissue, showing a pattern comparable to that obtained with fibronectin and collagen III. None of the pathological conditions displayed any peculiar character of CS distribution. This finding does not support a primary role for CS in the pathogenesis of muscular dystrophy.
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PMID:Immunohistochemical localization of chondroitin sulfate in normal and pathological human muscle. 308 12

The distribution pattern of fibronectin, laminin, type I, III and IV collagens in human skeletal muscle was studied by immunofluorescence. In normal muscle, as well as in congenital myopathies (CM), type I and III collagens were localized in the endomysium and the perimysium. Laminin and type IV collagen delineated precisely each muscle fiber but did not stain the perimysium. In Duchenne's muscular dystrophy (DMD) as well as in congenital muscular dystrophies (CMD) the extensive proliferation of connective tissue consisted mainly of fibronectin and type I and III collagens. Laminin and type IV collagen delineated principally the basal lamina but suprisingly were found to be distributed to some extent all over the extracellular matrix. No disease--specific accumulation of components of the extracellular matrix was found which would enable us to differentiate these last two diseases, though the immunofluorescence reactions for all components were stronger in DMD than in CMD.
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PMID:Fibronectin, laminin, type I, III and IV collagens in Duchenne's muscular dystrophy, congenital muscular dystrophies and congenital myopathies: an immunocytochemical study. 316 92

A 20-year-old patient was born with epidermolysis bullosa and a severe, slowly progressive muscle disease. Skin biopsy demonstrated junctional epidermolysis bullosa. Muscle biopsy demonstrated degenerative changes with increase in connective tissue, fibre size variability, rods and cytoplasmic bodies, central nuclei. In muscle biopsy dystrophin, chondroitin unsulphate, chondroitin 4-sulphate, chondroitin 6-sulphate, heparan sulphate, collagen III, collagen IV and VI, laminin, and fibronectin were normally distributed. This is the first report of the association of a form of congenital muscular dystrophy with junctional epidermolysis bullosa and, together with the previous reports of muscle involvement in epidermolysis bullosa simplex and dystrophica, it suggests the existence of a syndrome characterized by the contemporaneous presence of skin and muscle involvement.
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PMID:Congenital muscular dystrophy associated with familial junctional epidermolysis bullosa letalis. 830 68

We recently reported the selective reduction of the B1 subunit of laminin in two Japanese patients with adhalin deficiency. We here investigated immunohistochemically the expression of other components of the extracellular matrix (ECM), including collagen type IV, heparan sulfate proteoglycan can (HSPG), chondroitin-4-sulfate proteoglycan, decorin, and fibronectin in adhalin deficiency, compared with other types of muscular dystrophy. We found a reduction of HSPG on the basal lamina surrounding each muscle fiber in adhalin deficiency compared with HSPG in other diseases. This finding may be characteristic evidence of the disturbance of the sarcolemma-ECM interaction and the sarcolemmal instability in adhalin deficiency. Recently, a direct role of HSPG in fibroblast growth factor (FGF) signal transduction was demonstrated. Further investigation is required to determine if the dysfunction of FGF is relevant to the pathogenesis of adhalin deficiency.
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PMID:Abnormal expression of heparin sulfate proteoglycan on basal lamina of muscle fibers in two Japanese patients with adhalin deficiency. 858 Jul 28

The dy/dy mouse is an animal model for human merosin-negative congenital muscular dystrophy (CMD), which has been reported to have reduced or no expression of the basement membrane protein laminin alpha2. We here investigate various myogenic and nonmyogenic tissues of mature dy/dy and control 129ReJ mice histologically and for laminin alpha2 expression. In addition, expression patterns of laminin alpha1, alpha2, alpha4, and alpha5 chains, the interstitial proteins fibronectin and tenascin-C, and the adhesion molecules VCAM-1, ICAM-1, and alpha4 integrin were characterized in skeletal muscle of 1- and 7-day and mature (>6 weeks old) dy/dy and control 129ReJ mice. The laminin alpha2 chain remained detectable in myogenic tissues of dy/dy mice by immunofluorescence using two different monoclonal antibodies and by Northern blot analysis. However, laminin alpha2 expression was significantly reduced or not detectable in nonmyogenic tissues of dy/dy mice, including skin, lung, kidney, brain, thymus, and eye. Focal lesions were observed in mature skeletal muscle only, characterized by necrotic tissue, isolated VCAM-1- and ICAM-1-positive cells indicative of inflammatory processes, and regenerating muscle fibers surrounded by intense tenascin-C and fibronectin expression. In contrast to studies on human CMD muscle, laminin alpha1 was not detectable in either dy/dy or control skeletal muscle using immunofluorescence or Northern blot analysis. Immunofluorescence localized laminin alpha4 to basement membranes of blood vessels, the endoneurium of the intramuscular nerves, and the neuromuscular junction in skeletal muscle of 1- and 7-day-old dy/dy and control mice. In mature muscle, laminin alpha4 expression shifted to the perineurium of intramuscular nerves in both dy/dy and control mice. Furthermore, strong upregulation of laminin alpha4 in the basement membranes of blood vessels, the perineurium of intramuscular nerves, and of isolated regenerating muscle fibers in the dy/dy mice was apparent. Investigation of 1-day-old animals revealed expression of laminin alpha5 in skeletal muscle fiber basement membranes of dy/dy but not control animals. This difference between dy/dy and control animals was no longer apparent at 7 days after birth, indicating a temporary shift in expression pattern of laminin alpha5 in dy/dy animals. Analysis of the extracellular matrix components of 1- and 7-day-old dy/dy and control skeletal muscle revealed an early onset of the dystrophy, even before histopathological features of the disease were evident. Our data confirm the absence of laminin alpha1 chain in myogenic tissues of both dy/dy and control mice and suggest compensation for reduced laminin alpha2 in dy/dy skeletal muscle by laminin alpha4 and, in early development, also laminin alpha5. These results have significant ramifications in the diagnosis of human merosin-negative CMD.
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PMID:Expression of laminin alpha1, alpha2, alpha4, and alpha5 chains, fibronectin, and tenascin-C in skeletal muscle of dystrophic 129ReJ dy/dy mice. 988 26

The mdx mouse, an animal model of Duchenne muscular dystrophy, develops an X-linked recessive inflammatory myopathy. During onset of disease and height of myonecrosis, mdx mice also display important changes in the microenvironment of lymphoid tissues. Draining lymph nodes showed reduced cellularity and atrophy accompanied by intense immunolabeling for fibronectin, laminin, and type-IV collagen. Following clinical amelioration of dystrophy, mdx mice showed enhanced cellularity and a consistent increase in the absolute numbers of CD4(+) and CD8(+) cells expressing alpha4(high) and alpha5(high) extracellular matrix receptors. Furthermore, infiltrating cells in the proximity of myonecrosis expressed alpha4, alpha5, and alpha6 integrin chains during both height of myonecrosis and muscular tissue regeneration. Such results indicate that during distinct phases of muscular dystrophy, altered expression of extracellular matrix ligands and receptors may be influencing myonecrosis by promoting adhesion and migration of mononuclear cells into the altered skeletal muscle and toward local draining lymphoid tissue.
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PMID:Expression of extracellular matrix ligands and receptors in the muscular tissue and draining lymph nodes of mdx dystrophic mice. 1052 90

To examine the role of extracellular matrix (ECM)/integrin interactions in myelination we have analyzed oligodendrocyte differentiation and myelin membrane formation in oligodendrocytes grown in cell culture. We have found that the ECM substrates fibronectin, vitronectin, and laminin-2 (merosin) have no effect on differentiation, as measured by the appearance of myelin basic protein-expressing cells, but that laminin-2 substrates dramatically enhance myelin membrane formation. Blocking antibody and immunolocalization studies suggest that this effect is mediated via 1 integrins. The v integrins expressed on oligodendrocytes, in contrast, are less effective at promoting membrane formation. These results show that the interaction between laminin-2 expressed in white matter tracts and oligodendrocyte laminin-binding integrins may be an important part of the signalling mechanisms that stimulate oligodendrocytes to elaborate the extensive myelin membrane required to wrap the axon and form the myelin sheath. The results also provide a logical explanation for the abnormalities of myelination observed in humans with merosin-deficient congenital muscular dystrophy.
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PMID:Laminin-2/integrin interactions enhance myelin membrane formation by oligodendrocytes. 1057 90

Ullrich's disease is a congenital muscular dystrophy characterized clinically by generalized muscle weakness, multiple contractures of the proximal joints, and hyperextensibility of the distal joints. Recent studies have demonstrated that collagen VI is deficient in the muscles of patients with Ullrich's disease, and some cases result from recessive mutations of the collagen VIalpha2 gene (COL6A2). Fibronectin is one of the main components of the extracellular matrix (ECM) and associates with a variety of other matrix molecules including collagen. The behavior of fibronectin on cells is mediated by fibronectin receptors, members of the integrin family. We studied the expression of fibronectin receptors and fibronectin in patients with Ullrich's disease, and found a marked reduction of fibronectin receptors in the ECM of skin and cultured fibroblasts of these patients. These results suggest that collagen VI deficiency may lead to the reduction of fibronectin receptors and that an abnormality of cell adhesion may be involved in the pathogenesis of Ullrich's disease.
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PMID:Fibronectin receptor reduction in skin and fibroblasts of patients with Ullrich's disease. 1240 92

Force transmission at the myotendinous junction requires a strong link between the muscle cytoskeleton and the extracellular matrix. At the adult junction, two splice variants of the laminin-binding integrins, alpha7Abeta1D and alpha7Bbeta1D, are highly enriched. The alpha7 subunits are critical for the integrity of the junctional sarcolemma because integrin alpha7-deficient mice develop muscular dystrophy, primarily affecting this site of the muscle. Here, we report that beta1D integrin coimmunoprecipitates and colocalizes with the alpha5 subunit at alpha7-deficient junctions, but does not associate with alpha3, alpha6 or alphav integrins. By immunogold labelling we show that the basement membranes of integrin alpha7-deficient muscles recruit abnormally high levels of fibronectin, the ligand of alpha5beta1D. Finally, we demonstrate that alpha5beta1D is down-regulated at the normal postnatal junction and is displaced by alpha7beta1D. These results suggest that the alpha7 subunit is implicated in the down-regulation of alpha5beta1D and in the removal of fibronectin from the maturing myotendinous junction, thus providing an alpha7beta1D-based link to laminin. We propose that the persistence of alpha5beta1D in alpha7-deficient mice is not compatible with normal muscle function and leads to muscle wasting.
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PMID:Defective integrin switch and matrix composition at alpha 7-deficient myotendinous junctions precede the onset of muscular dystrophy in mice. 1258 96

Sequential activation of muscle-specific transcription factors is the critical basis for myogenic differentiation. However, the complexity of this process does not exclude the possibility that other molecules and systems are regulatory as well. We observed that myogenic differentiation proceeded through three distinct stages of proliferation, elongation and fusion, which are distinguishable by their cellular morphologies and gene expression patterns of proliferation- and differentiation-specific markers. Treatment of the differentiating myoblasts with inhibitors of matrix metalloproteinases (MMPs) revealed that MMP activity at the elongation stage is a critical prerequisite to complete the successive myoblast cell fusion. The MMP regulated the myogenic differentiation independently from the genetic program that governs expression of the myogenic genes. Membrane-type 1 matrix metalloproteinase (MT1-MMP) was identified as a major contributor to this checkpoint for morphological differentiation and degraded fibronectin, a possible inhibitory factor for myogenic cell fusion. A MT1-MMP deficiency caused similar myogenic impediments forming smaller myofibers in situ. Additionally, the mutant mice demonstrated some central nucleation of the myofibers typically found in muscular dystrophy and MT1-MMP was found to cleave laminin-2/4 in the basement membrane. Thus, MT1-MMP is a new multilateral regulator for muscle differentiation and maintenance through processing of stage-specific distinct ECM substrates.
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PMID:Multifunctional roles of MT1-MMP in myofiber formation and morphostatic maintenance of skeletal muscle. 1692 91


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