• Login
    View Item 
    •   Home
    • Brock Theses
    • Masters Theses
    • M.Sc. Applied Health Sciences
    • View Item
    •   Home
    • Brock Theses
    • Masters Theses
    • M.Sc. Applied Health Sciences
    • View Item
    JavaScript is disabled for your browser. Some features of this site may not work without it.

    Browse

    All of BrockUCommunitiesPublication DateAuthorsTitlesSubjectsThis CollectionPublication DateAuthorsTitlesSubjectsProfilesView

    My Account

    LoginRegister

    Statistics

    Display statistics

    GSK3 signalling in DBA/2J mdx mice: a comparison against the traditional C57BL/10 mdx model and investigation into its pathogenic contribution

    • CSV
    • RefMan
    • EndNote
    • BibTex
    • RefWorks
    Thumbnail
    Name:
    Brock_Whitley_Kennedy_2021.pdf
    Size:
    1.901Mb
    Format:
    PDF
    Download
    Author
    Whitley, Kennedy
    Keyword
    muscular dystrophy
    mdx
    tideglusib
    muscle wasting
    Duchenne's
    
    Metadata
    Show full item record
    URI
    http://hdl.handle.net/10464/15746
    Abstract
    Duchenne muscular dystrophy (DMD) is an X-linked disorder caused by an absence of dystrophin that compromises membrane integrity, ultimately resulting in muscle weakness, wasting and premature death. There is currently no cure for DMD, however, promoting the slow oxidative fibre type and reducing inflammation in muscle has become a viable therapeutic strategy. In this thesis, the role of glycogen synthase kinase 3 (GSK3) in DMD pathology, as it relates to inflammation and muscle fibre type composition, was examined. Specifically, the purpose of this thesis was to first characterize GSK3 signalling in two mdx mouse models of DMD, the traditional C57BL/10 (BL10) mdx mouse and the more severe DBA/2J (D2) mdx mouse model. Next, it was examined whether inhibiting GSK3 with a clinically relevant drug called tideglusib would promote the slow oxidative fibre type, reduce inflammation and ultimately enhance muscle structure and function in the D2 mdx mouse. In the first objective of this thesis, it was found that total GSK3 was significantly higher in extensor digitorum longus (EDL) muscles from D2 mice compared with BL10 mice. Inhibitory serine9 phosphorylation of GSK3 was also significantly lower in D2 mice compared with BL10 mice, suggestive of a strain effect whereby D2 mice had more active GSK3. In the second objective of this thesis, it was found short-term (2-4 weeks) tideglusib treatment (10 mg/kg/day) increased EDL:body mass ratio and reduced serum creatine kinase levels compared with vehicle control. Tideglusib treatment also enhanced muscle function with a significant improvement in hangwire impulse, and EDL specific force production and fatigue resistance. In the EDL muscles, tideglusib treatment reduced total GSK3, a result that was associated with an increase in the proportion of oxidative type I and IIa fibres and elevated utrophin mRNA expression. However, tideglusib treatment did not alter inflammatory cytokine expression of IL-1 and TNF-. Collectively, these results show that GSK3 activation may contribute to dystrophic pathology in the D2 mdx mouse and that short-term tideglusib treatment can inhibit GSK3 in these mice leading to a promotion of the oxidative fibres and an improvement in muscle form and function.
    Collections
    M.Sc. Applied Health Sciences

    entitlement

     
    DSpace software (copyright © 2002 - 2023)  DuraSpace
    Quick Guide | Contact Us
    Open Repository is a service operated by 
    Atmire NV
     

    Export search results

    The export option will allow you to export the current search results of the entered query to a file. Different formats are available for download. To export the items, click on the button corresponding with the preferred download format.

    By default, clicking on the export buttons will result in a download of the allowed maximum amount of items.

    To select a subset of the search results, click "Selective Export" button and make a selection of the items you want to export. The amount of items that can be exported at once is similarly restricted as the full export.

    After making a selection, click one of the export format buttons. The amount of items that will be exported is indicated in the bubble next to export format.