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)

Myotonic muscular dystrophy is an autosomal dominant defect that produces muscle wasting, myotonia, and cardiac conduction abnormalities. The myotonic dystrophy locus codes for a putative serine-threonine protein kinase of unknown function. We report that overexpression of human myotonic dystrophy protein kinase induces the expression of skeletal muscle-specific genes in undifferentiated BC3H1 muscle cells. BC3H1 clones expressing myotonic dystrophy kinase appear equivalent to differentiated cells with respect to expression of myogenin, retinoblastoma tumor supressor gene, M creatine kinase, beta-tropomyosin, and vimentin. In addition, differential display analysis demonstrates that the pattern of gene expression exhibited by myotonic dystrophy kinase-expressing cells is essentially identical to that of differentiated BC3H1 muscle cells. These observations suggest that myotonic dystrophy kinase may function in the myogenic pathway.
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PMID:Overexpression of myotonic dystrophy kinase in BC3H1 cells induces the skeletal muscle phenotype. 855 Jun 17

Myogenic regulatory factors (MRFs) promote differentiation of muscle cells from fibroblasts and are induced by insulin-like growth factor I (IGF-1). Prior studies have shown synthesis of new muscle protein and improved muscle morphology when mature dy mice with muscular dystrophy are treated with IGF-1. We investigated whether these salutary effects of IGF-1 might be attributable to stimulation of MRFs. Male dy (129ReJ) mice and controls (129J) were assigned to IGF-1 treatment (10 micrograms twice daily) or non-treatment at about 5 weeks of life and sacrificed 6 weeks later. RNA was extracted from skeletal muscles, reverse transcribed, and amplified by polymerase chain reaction (PCR) using primers specific for each MRF. Competitive PCR was performed to quantify MyoD expression in response to IGF-1 treatment. Transcripts for myf-5, MRF4, and myogenin were detected in both control and dy mouse muscles; no apparent differences were observed between treatment groups. Quantitative analysis of transcripts for MyoD indicated no significant basal differences between control and dy mice. There was, however, significantly higher MyoD expression in the dy group, and a trend toward significance in the control group, following IGF-1 treatment. These data suggest that IGF-1 exerts its in vivo effects in postembryonal muscle by stimulating MRFs.
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PMID:Expression of myogenic regulatory factors in normal and dystrophic mice: effects of IGF-1 treatment. 916 95

Caveolin-3 protein is the only member of the caveolin family that shows a unique muscle-specific expression pattern, and loss of its functional activity causes muscular dystrophy. Caveolin-3 mRNA levels are dramatically increased during the formation of myotubes in the C2C12 cell line. In this study, we characterized the human caveolin-3 5'-flanking region. Promoter analyses demonstrate that the proximal E box element serves as a myogenin binding site and is both necessary and sufficient to control caveolin-3 gene transcription. Transient transfection assays indicated that overexpression of myogenin activates caveolin-3 reporter gene expression, whereas Id2 overexpression inhibited caveolin-3 promoter activation by myogenin. A mutant Id2 protein lacking the HLH domain was not capable of suppressing myogenin-mediated activation. Determination of caveolin-3 transcript distribution patterns in vivo revealed that mRNA was first detectable at day 10 of gestation in the developing somites and heart. Caveolin-3 protein in myoblasts and myotubes was expressed in both the plasma membrane and vesicular structures. During skeletal myogenesis the level of Id2, an inhibitor of differentiation, decreases, allowing the induced basic helix-loop-helix transcription factor myogenin to form transcriptionally active heterodimers that bind to the caveolin-3 promoter and thereby mediate its transcription.
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PMID:The basic helix-loop-helix transcription factors myogenin and Id2 mediate specific induction of caveolin-3 gene expression during embryonic development. 1083 21

We recently developed a new cDNA microarray encompassing more than 5,000 genes expressed in human skeletal muscle. We successfully identified the differences at the gene expression profiles among Duchenne muscular dystrophy patients. Using our microarray, we catalogued gene expression during myogenic differentiation. The resultant expression patterns were classified into eight groups by hierarchical cluster analysis. Among them, clusters 6, 7, and 8 contain genes which show high expression level at the later differentiation stage and encode mainly sarocmere and extracellular matrix proteins. We used genes in these clusters as markers for regeneration. We identified that these regeneration-associated genes were not necessarily upregulated in Fukuyama congenital muscular dystrophy (FCMD) even though necrosis-associated genes were highly upregulated, suggesting the insufficient regenerating capability in FCMD. We have also characterized genes regulated by IGF-I simulation. We subject cascade specific inhibitors and IGF-I to human myotubes and performed gene expression profiling using our cDNA microarray. We found that PI3K/Akt-1 cascade first activates transcriptional factors such as MyoD, myogenin, and MEF2C, and then genes in clusters 6, 7, and 8, which have E-box and MEF-box where these transcriptional factors associate. We expect to develop a new therapeutic method by elucidating the molecular mechanism of muscular dystrophy and the effect of IGF-I and anti-myostatin treatments.
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PMID:[The pathomechanism and the direction of therapy development in view of cDNA microarray]. 1565 27

Caveolin-3 (Cav-3) is a principal structural protein of caveolae membrane domains. Animal studies have revealed that Cav-3 is expressed in skeletal and cardiac myocytes but absent in other types of cells. Recent studies have shown that abnormalities in the Cav-3 gene are associated with some forms of muscular dystrophy, while skeletal muscle abnormalities have been observed in Cav-3 transgenic and knockout mice. In this study the authors evaluated the distribution of Cav-3 in normal human tissues and compared the expression of Cav-3 with that of myogenin and myoD1 in rhabdomyosarcoma (RMS), malignant mixed mullerian tumor (MMMT), and an array of neoplasms that mimic RMS to assess the utility of Cav-3 as a diagnostic marker for tumors with skeletal muscle differentiation. In nonneoplastic human tissues, crisp membrane staining for Cav-3 was present in cardiac and skeletal myocytes and occasionally in arterial smooth muscle cells and prostatic stromal cells, while other cell types were negative for Cav-3. Eighty-eight percent (21/24) of RMS studied were positive for Cav-3. Positive staining was generally observed in the more maturely differentiated tumor cells but not the primitive tumor cells. Eight of nine cases of MMMT stained strongly with Cav-3 in their rhabdomyosarcomatous component but not in other components. Fifty-four other neoplasms (13 leiomyosarcomas, 8 neuroblastomas, 5 lymphomas, 6 Wilms tumors without skeletal muscle differentiation, 5 Ewing sarcomas, 4 malignant fibrous histiocytomas, 4 angiosarcomas, 6 malignant melanomas, and 3 synovial sarcomas) were negative for Cav-3 expression. Nearly all (96% [23/24]) cases of RMS were positive for myogenin, while 88% (21/24) were positive for myoD1. Primitive tumor cells showed significantly increased expression of myoD1 and myogenin; conversely, more differentiated tumor cells were negative or weakly stained. The rhabdomyosarcomatous component of MMMT stained focally with myogenin and myoD1, in contrast to the strong Cav-3 labeling in these cells. These results demonstrate that Cav-3 is specifically expressed in human cardiac and skeletal myocytes. Furthermore, its high specificity and relatively high sensitivity (88%) for tumors with skeletal muscle differentiation suggest that Cav-3 is a valuable marker for these tumors and may be used to assess the degree of differentiation of RMS and to identify residual tumor cells in post-chemotherapy specimens.
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PMID:Caveolin-3 is a sensitive and specific marker for rhabdomyosarcoma. 1608 47

Mutations in dysferlin cause a type of muscular dystrophy known as dysferlinopathy. Dysferlin may be involved in muscle repair and differentiation. We compared normal human skeletal muscle cultures expressing dysferlin with muscle cultures from dysferlinopathy patients. We quantified the fusion index of myoblasts as a measure of muscle development and conducted optic and electronic microscopy, immunofluorescence, Western blot, flow cytometry, and real-time PCR at different developmental stages. Short interference RNA was used to corroborate the results obtained in dysferlin-deficient cultures. A luciferase reporter assay was performed to study myogenin activity in dysferlin-deficient cultures. Myoblasts fusion was consistently delayed as compared with controls whereas the proliferation rate did not change. Electron microscopy showed that control cultured cells at 10 days were fusiform, whereas dysferlin-deficient cells were star-shaped and large. After 15 days the normal multinucleated appearance and structured myofibrils were not present in dysferlin-deficient cells. Strikingly, myogenin was not detected in myotubes from dysferlin-deficient cultures using Western blot, and mRNA analysis showed low levels (p < 0.05) compared with controls. Flow cytometry and immunofluorescence also showed reduced levels of myogenin in dysferlin-deficient cultures. When the dysferlin gene was knocked down ( approximately 80%), myogenin mRNA leveled down to approximately 70%. MyoD and desmin mRNA levels in controls and dysferlin-deficient cultures were similar. The reporter luciferase assay demonstrated a low myogenin activity in dysferlin-deficient cultures. These results point to a functional link between dysferlin and myogenin, and both proteins may share a new signaling pathway involved in differentiation of skeletal muscle in vitro.
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PMID:Absence of dysferlin alters myogenin expression and delays human muscle differentiation "in vitro". 1660 42

Myogenesis is one of the critical developmental processes in mammals. Several transcription factors from the dermomyotome affect embryonic myogenesis. Among these, Dmrt2 and Pax3 were tested for genetic and functional interactions during embryonic myogenesis by evaluating myogenin and desmin expression patterns in Dmrt2-Pax3 mutant mouse embryos. In doubly homozygous mutant embryos, myogenin expression was reduced, and the expression pattern was altered dramatically. In Pax3-knockout mouse embryos, the pattern of Dmrt2 expression was altered, suggesting that Pax3 is important in maintaining the epaxial dermomyotome. Even though Pax3 and Dmrt2 are expressed in similar tissue- and developmental-stage-specific manners during dermomyotomal development, they appear to have independent roles in mammalian myogenesis. The processes characteristic of embryonic myogenesis are similar to those occurring during muscle regeneration in adults. Therefore, these results may provide insight into the pathogenesis of innate muscular dystrophy and may lead to the development of drugs to promote muscle repair after injury.
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PMID:Dmrt2 and Pax3 double-knockout mice show severe defects in embryonic myogenesis. 1797 28

Nitric oxide (NO) mediates activation of satellite precursor cells to enter the cell cycle. This provides new precursor cells for skeletal muscle growth and muscle repair from injury or disease. Targeting a new drug that specifically delivers NO to muscle has the potential to promote normal function and treat neuromuscular disease, and would also help to avoid side effects of NO from other treatment modalities. In this research, we examined the effectiveness of the NO donor, iosorbide dinitrate (ISDN), and a muscle relaxant, methocarbamol, in promoting satellite cell activation assayed by muscle cell DNA synthesis in normal adult mice. The work led to the development of guaifenesin dinitrate (GDN) as a new NO donor for delivering nitric oxide to muscle. The results revealed that there was a strong increase in muscle satellite cell activation and proliferation, demonstrated by a significant 38% rise in DNA synthesis after a single transdermal treatment with the new compound for 24 h. Western blot and immunohistochemistry analyses showed that the markers of satellite cell myogenesis, expression of myf5, myogenin, and follistatin, were increased after 24 h oral administration of the compound in adult mice. This research extends our understanding of the outcomes of NO-based treatments aimed at promoting muscle regeneration in normal tissue. The potential use of such treatment for conditions such as muscle atrophy in disuse and aging, and for the promotion of muscle tissue repair as required after injury or in neuromuscular diseases such as muscular dystrophy, is highlighted.
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PMID:Development of a nitric oxide-releasing analogue of the muscle relaxant guaifenesin for skeletal muscle satellite cell myogenesis. 1931 16

We examine the potential for erythropoietin signaling to promote donor cell survival in a model of myoblast transplantation. Expression of a truncated erythropoietin receptor in hematopoietic stem cells has been shown to promote selective engraftment in mice. We previously demonstrated expression of endogenous erythropoietin receptor on murine myoblasts, and erythropoietin treatment can stimulate myoblast proliferation and delay differentiation. Here, we report that enhanced erythropoietin receptor expression, as well as exogenous erythropoietin treatment in myoblasts, provided a survival advantage and protection against apoptosis under serum-starvation conditions. When cultured in differentiation medium, expression of the myogenic regulatory proteins shifted toward early differentiation with increased erythropoietin receptor. Expression of early myogenic differentiation proteins Myf-5 and MyoD increased, while later stage protein myogenin decreased. Transplantation of C2C12 myoblasts overexpressing truncated erythropoietin receptor showed more transplanted cell incorporation into muscle fibers in muscular dystrophy mdx mice. These cells also restored dystrophin protein expression in mdx mice at 6 wk after cell treatment that was further increased with exogenous erythropoietin administration. In summary, enhanced erythropoietin receptor expression promotes transplanted cell survival in a mouse model for myoblast transplantation and provides dystrophin expression in mice with muscular dystrophy.
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PMID:Erythropoietin signaling promotes transplanted progenitor cell survival. 1941 86

The therapeutic effect of Glatiramer acetate, an immune modulating agent, was evaluated in the dy(2J)/dy(2J) mouse with merosin deficient congenital muscular dystrophy, which is a milder variant of the dy/dy mouse. The treated mice showed significant improvement in hind limb muscle strength measured by electronic grip strength meter and in motor performance quantified by video detection software. Glatiramer acetate treatment was associated with significantly increased expression of regeneration transcription factors MyoD and myogenin, and attenuation of the fibrosis markers vimentin and fibronectin. No effective treatment is currently available in congenital muscular dystrophy and Glatiramer acetate may present a new potential treatment for this disorder.
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PMID:Improved muscle strength and mobility in the dy(2J)/dy(2J) mouse with merosin deficient congenital muscular dystrophy treated with Glatiramer acetate. 2030 48


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