Publication Date
2021
Document Type
Dissertation
Committee Members
Andrew A. Voss, Ph.D. (Advisor); Mark M. Rich, M.D., Ph.D. (Committee Member); David R. Ladle, Ph.D. (Committee Member); Michael Leffak, Ph.D. (Committee Member); Dan R. Halm, Ph.D. (Committee Member)
Degree Name
Doctor of Philosophy (PhD)
Abstract
Huntington’s disease (HD) has classically been categorized as a neurodegenerative disorder. However, the expression of the disease-causing mutated huntingtin gene in skeletal muscle may contribute to the symptoms of HD, namely those that involve involuntary muscle contraction. In the R6/2 transgenic mouse model of HD, we previously observed ion channel defects that could contribute to involuntary muscle contraction. Here, in R6/2 muscle we investigated the consequence of these ion channel defects on action potentials (APs), the first step in excitation-contraction (EC) coupling. We found that the ion channel defects were associated with depolarizing the baseline membrane potential during AP trains. We also observed changes in the AP waveform in R6/2 muscle, including a prolonged falling phase, which was associated with reduced K + channel expression (another ion channel defect). Next, we investigated the consequence of prolonged APs on intracellular Ca 2+ release flux, the second step in EC coupling. We observed an increase in Ca 2+ release flux duration, which compensated for a reduction in peak Ca 2+ release flux, resulting in normal levels of Ca 2+ available for contraction in R6/2 muscle. Finally, we investigated the consequence of prolonged APs and normal levels of Ca 2+ available for contraction on muscle force generation, the final step in EC coupling. We found that, when accounting for muscle atrophy, the force generated by one AP (twitch) was normal in R6/2 mice. This could be explained by the reduced parvalbumin and normal levels of Ca 2+ available for contraction we observed in R6/2 muscle. We conclude that downregulation of K + channels to prolong APs is a compensatory mechanism for muscle weakness that leads to increased Ca 2+ release duration and force production in R6/2 muscle. This is the first study to examine the entire EC coupling sequence in HD muscle, revealing the importance of the AP waveform in contributing to muscle force generation.
Page Count
157
Department or Program
Biomedical Sciences
Year Degree Awarded
2021
Copyright
Copyright 2021, some rights reserved. My ETD may be copied and distributed only for non-commercial purposes and may not be modified. All use must give me credit as the original author.
Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-Share Alike 3.0 License.
