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

Plectin (M(r) > 500,000) is a versatile and widely expressed cytolinker protein. In striated muscle it is predominantly found at the Z-disc level where it colocalizes with the intermediate filament protein desmin. Both proteins show altered labeling patterns in tissues of muscular dystrophy patients. Moreover, mutations in the plectin gene lead to the autosomal recessive human disorder epidermolysis bullosa simplex with muscular dystrophy, and defects in the desmin gene have been shown to cause familiar cardiac and skeletal myopathy. Since intermediate filaments (IFs) in striated muscle tissue have been found to be intimately associated with mitochondria, we investigated whether plectin is involved in this association. Using postembedding immunogold labeling of Lowicryl sections and immunogold labeling of ultrathin cryosections, we show that plectin is associated with desmin IFs linking myofibrils to mitochondria at the level of the Z-disc and along the entire length of the sarcomere. The localization of plectin label at the mitochondrial membrane itself was consistent with a putative linker function of plectin between desmin IFs and the mitochondrial surface. In mitochondrion-rich muscle fibers, both plectin and desmin were part of an ordered arrangement of mitochondrial side branches, which wound around myofibrils adjacent to the Z-discs and were anchored into a filamentous network transversing from one fibril to the other. The association of mitochondria with plectin and IFs was seen also in tissues without regular distribution patterns of mitochondria, such as heart muscle and neonatal skeletal muscle tissues. These data were supplemented with in vitro binding assays showing direct interaction of plectin with desmin via its carboxy-terminal IF-binding domain. As a cytolinker protein associated with mitochondria and desmin IFs, plectin could play an important role in the positioning and shape formation, in particular branching, of mitochondrial organelles in striated muscle tissues.
 ...
PMID:Association of mitochondria with plectin and desmin intermediate filaments in striated muscle. 1052 38

Bronchial smooth muscle (SM) mesenchymal cell precursors change their shape from round to spread/elongated while undergoing differentiation. Here we show that this change in cell shape induces the expression of laminin (LM) alpha2 chain not present in round mesenchymal cells. LM alpha2 expression is reversible and switched on and off by altering the cell's shape in culture. In comparison, the expression of LM beta1 and gamma1 remains unchanged. Functional studies showed that mesenchymal cell spreading and further differentiation into SM are inhibited by an antibody against LM alpha2. Dy/dy mice express very low levels of LM alpha2 and exhibit congenital muscular dystrophy. Lung SM cells isolated from adult dy/dy mice spread defectively and synthesized less SM alpha-actin, desmin, and SM-myosin than controls. These deficiencies were completely corrected by exogenous LM-2. On histological examination, dy/dy mouse airways and gastrointestinal tract had shorter SM cells, and lungs from dy/dy mice contained less SM-specific protein. The intestine, however, showed compensatory hyperplasia, perhaps related to its higher contractile activity. This study therefore demonstrated a novel role for the LM alpha2 chain in SM myogenesis and showed that its decrease in dy/dy mice results in abnormal SM.
 ...
PMID:Cell elongation induces laminin alpha2 chain expression in mouse embryonic mesenchymal cells: role in visceral myogenesis. 1060 45

Plectin is a high-molecular mass protein (approximately 500 kd) that binds actin, intermediate filaments, and microtubules. Mutations of the plectin gene cause a generalized blistering skin disorder and muscular dystrophy. In adult muscle, plectin is colocalized with desmin at structures forming the intermyofibrillar scaffold and beneath the plasma membrane. To study the involvement of plectin in myofibrillogenesis, we analyzed the spatial and temporal expression patterns of plectin in cultured differentiating human skeletal muscle cells and its relationship to desmin intermediate filaments during this process. Northern and Western blot analyses demonstrated that at least two different plectin isoforms are expressed at all developmental stages from proliferating myoblasts to mature myotubes. Using immunocytochemistry, we show that the localization of plectin dramatically changes from a network-like distribution into a cross-striated distribution during maturation of myocytes. Double immunofluorescence experiments revealed that desmin and plectin are colocalized in premyofibrillar stages and in mature myotubes. Interestingly, plectin was often found to localize to the periphery of Z-discs during the actual alignment of neighboring myofibrils, and an obvious cross-striated plectin staining pattern was observed before desmin was localized in the Z-disc region. We conclude that the association of plectin with Z-discs is an early event in the lateral alignment of myofibrils that precedes the formation of the intermyofibrillar desmin cytoskeleton.
 ...
PMID:Association of plectin with Z-discs is a prerequisite for the formation of the intermyofibrillar desmin cytoskeleton. 1078 Jun 62

To test the hypothesis that basic fibroblast growth factor and mast cells play a key role in the phenotypic differences between human dystrophinopathies and hypertrophic feline muscular dystrophy, serial sections of dystrophin-deficient, carrier and normal cat muscle biopsy specimens were examined. They were stained immunohistochemically for dystrophin and different markers of differentiation such as desmin, vimentin and utrophin. Basic fibroblast growth factor was increased in the myofibers of dystrophic cats compared to normal controls and carriers. An association of basic fibroblast growth factor with fiber regeneration and necrosis was shown. The amount of mast cells was markedly increased in muscle tissue of dystrophic cats with a clear predominance of tryptase-positive cells present in large amounts in the endomysium. Mast cells, like basic fibroblast growth factor, were concentrated in areas of muscle fiber regeneration and necrosis. Our data concerning basic fibroblast growth factor and mast cells are consistent with a highly abnormal cellular environment in feline dystrophic muscle with very high levels of basic fibroblast growth factor which is likely modulated by mast cells.
 ...
PMID:Mast cell proliferation and alterations in bFGF amount and localization are involved in the response of muscle to dystrophin deficiency in hypertrophic feline dystrophy. 1116 67

Dilated cardiomyopathy is one of the leading causes of heart failure and a primary cause for heart transplantation in patients below the age of 40 years. Despite major advances in diagnostic procedures such as examination of myocardial biopsies, the etiology remains unknown in many patients. Chronic inflammation or myocarditis and chronic alcohol abuse are considered two main etiologic factors in dilated cardiomyopathy. A third causal factor, namely genetic transmission of the disease, is at least as common as myocardial inflammation or toxic damage. Several prospective studies of relatives of patients with dilated cardiomyopathy proved that about 25-30% of all cases are of familial etiology. The most common mode of inheritance is autosomal dominant. Less frequently is the disease inherited as an X-chromosomal trait. Autosomal recessive and mitochondrial transmission is rare. The penetrance is highly variable and age dependent. Many relatives of patients with DCM show only minor cardiac abnormalities and it is unknown whether they progress to full cardiomyopathy in later life. Examination of families has identified so far eight disease genes, namely the dystrophin, tafazzin, cardiac actin, desmin, lamin A/C, delta- sarcoglycan, cardiac beta-myosin heavy chain, and cardiac troponin T gene. Certain mutations in lamin A/C cause conduction system disease and dilated cardiomyopathy, whereas other mutations cause in addition skeletal muscle myopathy. Dystrophin mutations are the cause of the rare X-linked dilated cardiomyopathy without skeletal muscle involvement and a progressive course in young men. Other mutations in the dystrophin gene, mainly deletions, are the cause of the muscular dystrophy Becker and Duchenne which also present with dilated cardiomyopathy. Mutations of the desmin, delta-sarcoglycan, the cardiac actin and beta-myosin heavy chain as well as the troponin T gene are known to cause autosomal dominant-dilated cardiomyopathy without other abnormalities. The infantile X-linked DCM is caused by mutations of the tafazzin gene. The onset of the disease is typically within the first year of life and death occurs usually in childhood. Most patients may in addition be characterized by skeletal myopathy, short stature, neutropenia and abnormal mitochondria, also referred to as Barth syndrome. Knowledge of the DCM disease genes led to the new hypothesis that dilated cardiomyopathy is a disease of the myocardial force generation or force transmission. Many more disease loci are known but the responsible disease genes are not yet identified. Better understanding of the expression and function of disease genes may eventually result in new diagnostic and therapeutic tools in order to improve the prognosis of this severe disorder.
 ...
PMID:[Genetics of dilated cardiomyopathy]. 1151 75

The myogenic potential of bone marrow and fetal liver cells was examined using donor cells from green fluorescent protein (GFP)-gene transgenic mice transferred into chimeric mice. Lethally irradiated X-chromosome-linked muscular dystrophy (mdx) mice receiving bone marrow cells from the transgenic mice exhibited significant numbers of fluorescence(+) and dystrophin(+) muscle fibres. In order to compare the generating capacity of fetal liver cells with bone marrow cells in neonatal chimeras, these two cell types from the transgenic mice were injected into busulfantreated normal or mdx neonatal mice, and muscular generation in the chimeras was examined. Cardiotoxin-induced (or -uninduced, for mdx recipients) muscle regeneration in chimeras also produced fluorescence(+) muscle fibres. The muscle reconstitution efficiency of the bone marrow cells was almost equal to that of fetal liver cells. However, the myogenic cell frequency was higher in fetal livers than in bone marrow. Among the neonatal chimeras of normal recipients, several fibres expressed the fluorescence in the cardiotoxin-untreated muscle. Moreover, fluorescence(+) mononuclear cells were observed beneath the basal lamina of the cardiotoxin-untreated muscle of chimeras, a position where satellite cells are localizing. It was also found that mononuclear fluorescence(+) and desmin(+) cells were observed in the explantation cultures of untreated muscles of neonatal chimeras. The fluorescence(+) muscle fibres were generated in the second recipient mice receiving muscle single cells from the cardiotoxin-untreated neonatal chimeras. The results suggest that both bone marrow and fetal liver cells may have the potential to differentiate into muscle satellite cells and participate in muscle regeneration after muscle damage as well as in physiological muscle generation.
 ...
PMID:Muscle regeneration by reconstitution with bone marrow or fetal liver cells from green fluorescent protein-gene transgenic mice. 1188 27

Mutations of the human plectin gene (Plec1) cause autosomal recessive epidermolysis bullosa simplex with muscular dystrophy (EBS-MD). Here, we report on molecular mechanisms leading to severe dystrophic muscle alterations in EBS-MD. Analysis of a 25-yr-old EBS-MD patient carrying a novel homozygous 16-bp insertion mutation (13803ins16/13803ins16) close to the intermediate filament (IF) binding site of plectin showed severe disorganization of the myogenic IF cytoskeleton. Intermyofibrillar and subsarcolemmal accumulations of assembled but highly unordered desmin filaments may be attributed to impaired desmin binding capability of the mutant plectin. This IF pathology was also associated with severe mitochondrial dysfunction, suggesting that the muscle pathology of EBS-MD caused by IF disorganization leads not only to defects in mechanical force transduction but also to metabolic dysfunction. Beyond EBS-MD, our data may contribute to the understanding of other myopathies characterized by sarcoplasmic IF accumulations such as desminopathies or alpha-B-crystallinopathies.
 ...
PMID:Disorganization of the desmin cytoskeleton and mitochondrial dysfunction in plectin-related epidermolysis bullosa simplex with muscular dystrophy. 1207 35

Alterations in mitochondrial distribution and morphology are associated with normal cellular processes such as cell division and differentiation, as well as a variety of pathological conditions, including muscular dystrophy and cardiomyopathy. These observations have illuminated the necessity for a cellular machinery that mediates mitochondrial behavior and function. One important candidate member of this machinery is the cytoskeleton, all three members of which seem to associate with mitochondria. The role and significance of such association with the intermediate filament (IF) cytoskeleton in muscle was until recently completely unknown. Recent studies with desmin-deficient mice revealed the importance of desmin IFs in mitochondrial behavior and function. This review summarizes recent findings that link desmin cytoskeleton to muscle mitochondrial distribution and function. In particular, hypotheses are presented on the potential mechanism by which desmin's absence from cardiac muscle leads to abnormal mitochondrial behavior and compromised function, potentially responsible for the development of dilated cardiomyopathy and heart failure in desmin-null mice.
 ...
PMID:Desmin cytoskeleton: a potential regulator of muscle mitochondrial behavior and function. 1253 20

Deficiency of laminin alpha2 is the cause of one of the most severe muscular dystrophies in humans and other species. It is not yet clear how particular mutations in the laminin alpha2 chain gene affect protein expression, and how abnormal levels or structure of the protein affect disease. Animal models may be valuable for such genotype-phenotype analysis and for determining mechanism of disease as well as function of laminin. Here, we have analyzed protein expression in three lines of mice with mutations in the laminin alpha2 chain gene and in two lines of transgenic mice overexpressing the human laminin alpha2 chain gene in skeletal muscle. The dy(3K)/dy(3K) experimental mutant mice are completely deficient in laminin alpha2; the dy/dy spontaneous mutant mice have small amounts of apparently normal laminin; and the dy(W)/dy(W) mice express even smaller amounts of a truncated laminin alpha2, lacking domain VI. Interestingly, all mutants lack laminin alpha2 in peripheral nerve. We have demonstrated previously, that overexpression of the human laminin alpha2 in skeletal muscle in dy(2J)/dy(2J) and dy(W)/dy(W) mice under the control of a striated muscle-specific creatine kinase promoter substantially prevented the muscular dystrophy in these mice. However, dy(W)/dy(W) mice, expressing the human laminin alpha2 under the control of the striated muscle-specific portion of the desmin promoter, still developed muscular dystrophy. This failure to rescue is apparently because of insufficient production of laminin alpha2. This study provides additional evidence that the amount of laminin alpha2 is most critical for the prevention of muscular dystrophy. These data may thus be of significance for attempts to treat congenital muscular dystrophy in human patients.
 ...
PMID:Laminin alpha2 deficiency and muscular dystrophy; genotype-phenotype correlation in mutant mice. 1260 2

Plectin is a versatile cytoskeletal linker protein that preferentially localizes at interfaces between intermediate filaments and the plasma membrane in muscle, epithelial cells, and other tissues. Its deficiency causes muscular dystrophy with epidermolysis bullosa simplex. To better understand the functional roles of plectin beneath the sarcolemma of skeletal muscles and to gain some insights into the underlying mechanism of plectin-deficient muscular dystrophy, we studied in vivo structural and molecular relationships of plectin to subsarcolemmal cytoskeletal components, such as desmin, dystrophin, and vinculin, in rat skeletal muscles. Immunogold electron microscopy revealed that plectin fine threads tethered desmin intermediate filaments onto subsarcolemmal dense plaques overlying Z-lines and I-bands. These dense plaques were found to contain dystrophin and vinculin, and thus may be the structural basis of costameres. The in vivo association of plectin with desmin, (meta-)vinculin, dystrophin, and actin was demonstrated by immunoprecipitation experiments. Treatment of plectin immunoprecipitates with gelsolin reduced actin, dystrophin, and (meta-)vinculin but not desmin, implicating that subsarcolemmal actin could partly mediate the interaction between plectin and dystrophin or (meta-)vinculin. Altogether, our data suggest that plectin, along with desmin intermediate filaments, might serve a vital structural role in the stabilization of the subsarcolemmal cytoskeleton.
 ...
PMID:Plectin tethers desmin intermediate filaments onto subsarcolemmal dense plaques containing dystrophin and vinculin. 1261 Jul 30


<< Previous 1 2 3 4 5 6 Next >>