Three Dimensional Stochastic Computer Model of the Skeletal Muscle Half Sarcomere: changes in calcium diffusion caused by the myofilament lattice
Abstract
In this thesis a 3-dimensional model of the skeletal muscle myofibril is developed. This model uses a Monte-Carlo based algorithm to simulate diffusion and binding of individual calcium ions (Ca2+) through the skeletal muscle myofibrillar 1/2 sarcomere. This Ca2+ diffusion model is a departure from recent Ca2+ models, which use a series of ordinary differential equations to compute diffusion and binding.
The thesis begins with an overview of current understanding of muscle structure and activation. Emphasising the structure of the myofilament lattice (MFL), and our current ability to understand Ca2+ handling within the sarcomere.
We build virtual models of the MFL at lengths of 1.8, 2.3, and 2.8 µm, then demonstrate that changes in MFL spacing associated with changes in sarcomere length (SL), affect myosin and actin interaction. Using MCell™ software that incorporates the MFL, we reproduce the experimental and previous simulation results for an averaged calcium transient during a single activation. In addition, our simulation provided data which demonstrate how the MFL affects the diffusion and binding of Ca2+. This simulation model yielded advanced visualizations of this process; two simulation movies of excitation-contraction coupling. Modelling SLs of 1.8 and 2.8 µm we explore how changes in SL can influence the diffusion of Ca2+ following a simulated activation. At the shorter length of 1.8 µm, the greater filament overlap and larger interfilament spacing result in more even diffusion of Ca2+. Conversely, at 2.8 µm there was an anisotropic distribution of Ca2+ with higher [Ca2+] and greater Ca2+ binding to TnC observed closest to the Z-disk.
Finally, the position of the triad on the surface of the sarcomere model was altered to replicate amphibian muscle. Moving the triad to the amphibian muscle position increased the [Ca2+] transient by 56 % when compared with the mammalian placement. This change increases [Ca2+] in the centre of the sarcomere model with fewer Ca2+ able to bind TnC.
Description
Keywords
Bioinformatics, Physiology, Computer Science
Citation
Holash, R. J. (2017). Three Dimensional Stochastic Computer Model of the Skeletal Muscle Half Sarcomere: changes in calcium diffusion caused by the myofilament lattice (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca. doi:10.11575/PRISM/28434