Doran, Philip and Wilton, Steve D. and Fletcher, Sue and Ohlendieck, Kay (2009) Proteomic profiling of antisense-induced exon skipping reveals reversal of pathobiochemical abnormalities in dystrophic mdx diaphragm. Proteomics, 9 (3). pp. 671-685. ISSN 1615-9853

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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.

Item Type:	Article
Keywords:	antisense oligomer; DIGE; exon skipping; mdx; muscular dystrophy;
Academic Unit:	Faculty of Science and Engineering > Biology
Item ID:	7494
Identification Number:	https://doi.org/10.1002/pmic.200800441
Depositing User:	Prof. Kay Ohlendieck
Date Deposited:	07 Oct 2016 10:41
Journal or Publication Title:	Proteomics
Publisher:	Wiley
Refereed:	Yes
Funders:	Muscular Dystrophy Ireland, Science Foundation Ireland (SFI), National Institutes of Health, Muscular Dystrophy Association of USA, National Health and Medical Research Council, Health Research Board (HRB)
URI:	http://onlinelibrary.wiley.com
Use Licence:	This item is available under a Creative Commons Attribution Non Commercial Share Alike Licence (CC BY-NC-SA). Details of this licence are available here

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