Mark M. Rich, M.D., Ph.D. (Advisor); Brent Foy, Ph.D. (Committee Member); Lynn Hartzler, Ph.D. (Committee Member); Kathrin Engisch, Ph.D. (Committee Member); Andrew Ednie, Ph.D. (Committee Member)
Doctor of Philosophy (PhD)
Recent experimental findings in the Rich lab suggest there are important gaps in our understanding of muscle excitability in various disease states. To generate and test hypotheses as well as to determine whether our current understanding of various aspects of muscle excitation can fully explain experimental findings, an accurate model of muscle excitation was needed. Previous studies have modeled excitation of muscle, but in each case, important aspects were omitted. One reason for this is that little effort has been made to accurately simulate muscle action potentials. In this thesis I present progress made towards generation of a model of muscle excitation that more accurately simulates experimental data than any model to date. I began by accurately simulating the spatial arrangement of t-tubules based on recent detailed imaging studies of t-tubules performed in the Voss lab. This allowed examination of whether the reduction in t-tubule diameter in muscle from a mouse model of Huntington’s disease could account for the reduction in muscle capacitance. My simulations indicate the reduction in t-tubule diameter is insufficient to explain the reduction in capacitance and suggest there is an alteration of muscle membrane itself in Huntington’s disease. I next derived parameters used to simulate the behavior of ion channels involved in generation of action potentials. I did this by reverse engineering the parameters from action potentials recorded in the Rich lab. The derived parameters led to more accurate modeling of action potentials than previously possible. In addition, sensitivity analysis was performed to identify the key parameters that govern action potential characteristics. Finally, I combined t-tubule geometry with the accurately simulated action potentials to explore the currently accepted idea that action potential propagation into t-tubules is necessary for the process of excitation contraction coupling. My simulations suggest action potential-induced depolarization may spread to the center of fibers intracellularly such that action potential propagation into t-tubules is not necessary for excitation contraction coupling. If true, this would be a significant departure from the current understanding of the role of t-tubules in excitation contraction coupling. My model opens the way for future studies of dysregulation of muscle excitability in a number of different muscle diseases.
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Copyright 2021, all rights reserved. My ETD will be available under the "Fair Use" terms of copyright law.