Publication Date
2025
Document Type
Thesis
Committee Members
Mark M. Rich, M.D., Ph.D. (Advisor); Keiichiro Susuki, M.D., Ph.D. (Committee Member); Christopher N. Wyatt, Ph.D. (Committee Member)
Degree Name
Master of Science (MS)
Abstract
Myotonia congenita (MC) is a genetic disorder caused by loss-of-function mutations in the ClC-1 chloride channel, leading to muscle hyperexcitability and symptoms of transient stiffness and weakness. Work in hyperkalemic periodic paralysis (HKPP), a disorder with overlapping clinical features, has shown that myotonia can arise from two distinct mechanisms: a sustained form and a transient post-stimulus form, which have opposite temperature dependence. In HKPP, sustained myotonia worsens at elevated temperatures, whereas transient myotonia is exacerbated by cooling. This study tested whether these two mechanisms also contribute to myotonia in MC. Ex vivo force recordings were performed in extensor digitorum longus (EDL) muscles from two MC models: a genetic model lacking the CLCN1 gene and a pharmacological model in which the ClC-1 blocker 9-anthracenecarboxylic acid (9AC) was applied to wild-type muscle. Temperature dependence of sustained and transient myotonia was assessed across both models. In the genetic MC model, muscles showed evidence of impaired calcium handling, reflected by reduced force generation at low stimulation frequencies. Myotonia was dominated by the post-stimulus transient form, which was more pronounced in the genetic model and at room temperature. Spontaneous transient bursts of myotonic activity were also observed in MC muscles, although these were not statistically different from wild-type controls or the pharmacological model. Future work will increase sample size to clarify which differences are statistically significant. If indicated, intracellular recording will be performed to determine underlying mechanisms to follow the calcium flow throughout the muscle cell.
Page Count
78
Department or Program
Department of Neuroscience, Cell Biology, and Physiology
Year Degree Awarded
2025
Copyright
Copyright 2025, all rights reserved. My ETD will be available under the "Fair Use" terms of copyright law.
ORCID ID
0009-0001-3784-4798
