Journal article
Proteomic profiling of antisense-induced exon skipping reveals reversal of pathobiochemical abnormalities in dystrophic mdx diaphragm
Proteomics, Vol.9(3), pp.671-685
2009
Abstract
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, β-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.
Details
- Title
- Proteomic profiling of antisense-induced exon skipping reveals reversal of pathobiochemical abnormalities in dystrophic mdx diaphragm
- Authors/Creators
- P. Doran (Author/Creator) - National University of Ireland, MaynoothS.D. Wilton (Author/Creator) - The University of Western AustraliaS. Fletcher (Author/Creator) - The University of Western AustraliaK. Ohlendieck (Author/Creator) - National University of Ireland, Maynooth
- Publication Details
- Proteomics, Vol.9(3), pp.671-685
- Publisher
- John Wiley & Sons Ltd.
- Identifiers
- 991005542422607891
- Copyright
- © 2009 WILEY-VCH Verlag GmbH & Co.
- Murdoch Affiliation
- Murdoch University
- Language
- English
- Resource Type
- Journal article
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Source: InCites
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- Collaboration types
- Domestic collaboration
- International collaboration
- Citation topics
- 1 Clinical & Life Sciences
- 1.255 Musculoskeletal Disorders
- 1.255.628 Duchenne Muscular Dystrophy
- Web Of Science research areas
- Biochemical Research Methods
- Biochemistry & Molecular Biology
- ESI research areas
- Biology & Biochemistry