Accessibility navigation


Relationship between myosin heavy chain fibre type and restoration of dystrophin expression and key components of the dystrophin-associated glycoprotein complex by Tricyclo-DNA mediated exon skipping

Omairi, S., Hau, K.-L., Collins-Hooper, H., Montanaro, F., Goyenvalle, A., Garcia, L. and Patel, K. (2017) Relationship between myosin heavy chain fibre type and restoration of dystrophin expression and key components of the dystrophin-associated glycoprotein complex by Tricyclo-DNA mediated exon skipping. Molecular Therapy - Nucleic Acids, 9. pp. 409-418. ISSN 2162-2531

[img]
Preview
Text (Open Access) - Published Version
· Available under License Creative Commons Attribution.
· Please see our End User Agreement before downloading.

3MB
[img] Text - Accepted Version
· Restricted to Repository staff only
· Available under License Creative Commons Attribution Non-commercial No Derivatives.

3MB

It is advisable to refer to the publisher's version if you intend to cite from this work. See Guidance on citing.

To link to this item DOI: 10.1016/j.omtn.2017.10.014

Abstract/Summary

Exon skipping mediated by tricyclo-DNA (tc-DNA) antisense oligonucleotides has been shown to induce significant levels of dystrophin restoration in mdx, a mouse model of Duchenne Muscular Dystrophy. This translates into significant improvement in key disease indicators in muscle, cardio-respiratory function, heart and the central nervous system. Here we examine the relationship between muscle fibre type, based on Myosin Heavy chain profile, and the ability of tc-DNA to restore not only dystrophin but also other members of the dystrophin-associated glycoprotein complex (DAPC). We first profiled this relationship in untreated mdx muscle and found that all fibre types support reversion events to a dystrophin positive state, in an unbiased manner. Importantly, we show that only a small fraction of revertant fibres expressed other members of the DAPC. Immunoblot analysis of protein levels, however, revealed robust expression of these components, which failed to correctly localise to the sarcolemma. We then show that tc-DNA treatment leads to nearly all fibres expressing not only dystrophin but also other key components of the DAPC. Of significance, our work shows that MHC fibre type does not bias the expression of any of these important proteins. This work also highlights that the improved muscle physiology following tc-DNA treatment reported previously results from the complete restoration of the dystrophin complex in all MHCII fibres with equal efficiencies.

Item Type:Article
Refereed:Yes
Divisions:Faculty of Life Sciences > School of Biological Sciences > Biomedical Sciences
ID Code:73299
Publisher:Elsevier

Downloads

Downloads per month over past year

University Staff: Request a correction | Centaur Editors: Update this record

Page navigation