Show simple item record

dc.contributor.authorColeman, Andrew
dc.date.accessioned2022-06-22T19:38:36Z
dc.date.available2022-06-22T19:38:36Z
dc.date.issued2022
dc.identifier.urihttp://hdl.handle.net/10713/19242
dc.descriptionUniversity of Maryland, Baltimore. Molecular Medicine. Ph.D. 2022.en_US
dc.description.abstractMechanotransduction 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.en_US
dc.language.isoen_USen_US
dc.subject.meshAcetylationen_US
dc.subject.meshMicrotubulesen_US
dc.subject.meshMuscle Contractionen_US
dc.subject.meshMuscle, Striateden_US
dc.subject.meshMechanotransduction, Cellularen_US
dc.subject.meshTubulinen_US
dc.subject.meshMuscular Dystrophiesen_US
dc.titleInvestigating the Role of Acetylated Tubulin on Microtubule Dependent Mechanotransduction in Striated Muscleen_US
dc.typedissertationen_US
dc.date.updated2022-06-10T22:13:54Z
dc.language.rfc3066en
dc.contributor.advisorWard, Christopher, Ph.D.
dc.contributor.advisorLederer, W. Jonathan
refterms.dateFOA2022-06-22T19:38:37Z


Files in this item

Thumbnail
Name:
Coleman_umaryland_0373D_11349.pdf
Size:
6.017Mb
Format:
PDF

This item appears in the following Collection(s)

Show simple item record