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 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

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