• Login
    View Item 
    •   UMB Digital Archive
    • School, Graduate
    • Theses and Dissertations All Schools
    • View Item
    •   UMB Digital Archive
    • School, Graduate
    • Theses and Dissertations All Schools
    • View Item
    JavaScript is disabled for your browser. Some features of this site may not work without it.

    Browse

    All of UMB Digital ArchiveCommunitiesPublication DateAuthorsTitlesSubjectsThis CollectionPublication DateAuthorsTitlesSubjects

    My Account

    LoginRegister

    Statistics

    Display statistics

    Investigating the Role of Acetylated Tubulin on Microtubule Dependent Mechanotransduction in Striated Muscle

    • CSV
    • RefMan
    • EndNote
    • BibTex
    • RefWorks
    Thumbnail
    Name:
    Coleman_umaryland_0373D_11349.pdf
    Size:
    6.017Mb
    Format:
    PDF
    Download
    Author
    Coleman, Andrew
    Advisor
    Ward, Christopher, Ph.D.
    Lederer, W. Jonathan
    Date
    2022
    Type
    dissertation
    
    Metadata
    Show full item record
    Abstract
    Mechanotransduction is critical to the maintenance and development of striated muscle in response to a change in workload. Mechanical sensors within muscle respond to muscle movement to regulate EC coupling, gene expression, and signal propagation. Our lab has investigated the role of the cytoskeleton as a mechanosensor in striated muscle. Biophysical properties of microtubules (MTs) allow for mechanical energy created during sarcomere shortening to be transferred to the cytoskeleton network and associated proteins. Upon contraction or stretch, mechanical energy is transferred through the MT network to the membrane bound NADPH oxidase 2 (Nox2) to trigger a localized increase in reactive oxygen species (ROS) production that regulates calcium channels at the triad junction. This mechanotransduction pathway is regulated not only by the abundance of MT and Nox2, but also the biophysical properties of MTs. Post translational modifications to tubulin have various consequences to polymerized tubulin and create distinct subsets of MT populations within muscle. While MT acetylation of lysine 40 within the lumen of polymerized MTs is abundant in muscle, little is known about its function in muscle. Recent investigations that explored the biophysical properties of MT acetylation in vitro have shown that acetylation increases the resistance of MTs to damage by repeated mechanical insults. Here we sought to investigate the role of MT acetylation in muscle mechanotransduction in health and disease. Using Pharmacologic and genetic strategies, we show that microtubules enriched in acetylated α-tubulin increase cytoskeletal stiffness and viscoelastic resistance. These changes slow rates of contraction and relaxation during unloaded contraction and increased activation oof Nox2 by mechanotransduction. Importantly, MT acetylation had no effect on tension produced during contraction of intact muscle enabling enhanced mechanotransduction without altering force production. Furthermore, we show that microtubule PTMs are elevated in heart failure, muscular dystrophy, and aging. These changes translated to excess mechanotransduction and are potential therapeutic targets to diminish oxidative stress associated with muscle disease. Together, these findings add to growing evidence that microtubules contribute to the mechanobiology of striated muscle and are detrimental muscle disease modifiers.
    Description
    University of Maryland, Baltimore. Molecular Medicine. Ph.D. 2022.
    Keyword
    Acetylation
    Microtubules
    Muscle Contraction
    Muscle, Striated
    Mechanotransduction, Cellular
    Tubulin
    Muscular Dystrophies
    Identifier to cite or link to this item
    http://hdl.handle.net/10713/19242
    Collections
    Theses and Dissertations School of Medicine
    Theses and Dissertations All Schools

    entitlement

     
    DSpace software (copyright © 2002 - 2023)  DuraSpace
    Quick Guide | Policies | Contact Us | UMB Health Sciences & Human Services Library
    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.