Microtubule Regulation of Mitochondrial Bioenergetics in Cardiac and Skeletal Muscles

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dc.contributor.advisorPerry, Christopher G. R.
dc.contributor.authorRamos, Sofhia Verena
dc.date.accessioned2020-05-11T12:37:02Z
dc.date.available2020-05-11T12:37:02Z
dc.date.copyright2019-07
dc.date.issued2020-05-11
dc.date.updated2020-05-11T12:37:02Z
dc.degree.disciplineKinesiology & Health Science
dc.degree.levelDoctoral
dc.degree.namePhD - Doctor of Philosophy
dc.description.abstractA novel model of mitochondrial bioenergetic regulation has been proposed whereby microtubules may directly influence the permeability of ADP into the mitochondria to stimulate the production of ATP. Specifically, tubulin, the structural unit of microtubules, physically inserts into the voltage gated dependent anion channel (VDAC) embedded in planar lipid membranes which was speculated to prevent ADP/ATP cycling. Such regulation could be profound given ADP/ATP cycling kinetics determine the rate of oxidative phosphorylation and reactive oxygen species (ROS) emission key mitochondrial functions that are critical to muscle cells. VDAC is also believed to be central to the formation of the mitochondrial permeability transition pore (mPTP) which releases pro-apoptotic factors that trigger cell death. To date, a direct measure of a tubulin-VDAC interaction has yet to be demonstrated in cardiac and skeletal muscles, particularly in relation to mitochondrial bioenergetics. The primary objective of this thesis was to explore the tubulin-VDAC model of mitochondrial bioenergetic regulation in cardiac and skeletal muscles. This was achieved by employing pharmacological and genetic models of microtubule disorganization in an attempt to alter tubulin-VDAC interactions in relation to mitochondrial dysfunction. The results demonstrate that in-vitro paclitaxel treatment in extensor digitorum longus (EDL) muscle increases both - and II-tubulin-VDAC2 interaction while impairing some mitochondrial functions in partial support of the tubulin-VDAC model. The remaining data challenges this model. Specifically, cardiac muscle demonstrated a host of bioenergetic impairments in-vitro independent of a change in tubulin-VDAC interaction, while in-vivo treatment with paclitaxel, and vinblastine resulted in creatine independent mitochondrial impairments. Second, in-vivo paclitaxel administration surprisingly increased hind-limb torque and II-tubulin-VDAC2 interaction in soleus while eliciting minor inhibitions of ADP-dependent bioenergetic functions. In contrast, in-vivo administration of vinblastine caused muscle weakness and mitochondrial dysfunction in both soleus and white gastrocnemius, but did not change tubulin-VDAC2 interactions. Lastly, EDL muscles isolated from D2.mdx mouse model of disorganized microtubules and muscle weakness did not show altered tubulin-VDAC interactions despite the presence of mitochondrial dysfunctions. Overall, this thesis is the first to identify a direct - and II-tubulin interaction with VDAC2 in cardiac and skeletal muscle. While the data presented are not always in support of this model it raises new questions that challenges the regulation of this physical interaction in ADP diffusion regulation.
dc.identifier.urihttps://hdl.handle.net/10315/37354
dc.languageen
dc.rightsAuthor owns copyright, except where explicitly noted. Please contact the author directly with licensing requests.
dc.subjectHealth sciences
dc.subject.keywordsBioenergetics
dc.subject.keywordsMitochondria
dc.subject.keywordsPhysiology
dc.subject.keywordsSkeletal muscle
dc.subject.keywordsVDAC
dc.subject.keywordsTubulin
dc.subject.keywordsMicrotubules
dc.titleMicrotubule Regulation of Mitochondrial Bioenergetics in Cardiac and Skeletal Muscles
dc.typeElectronic Thesis or Dissertation

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