Browsing by Author "Holash, Robert John"

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    A Stochastic Simulation of Skeletal Muscle Calcium Transients in a Structurally Realistic Sarcomere Model using MCell
    (PLOS Computational Biology, 2019-01-30) Holash, Robert John; MacIntosh, Brian R.
    Skeletal muscle contraction is initiated when an action potential triggers the release of Ca2+ into the sarcomere in a process referred to as excitation-contraction coupling. The speed and scale of this process makes direct observation very challenging and invasive. To determine how the concentration of Ca2+changes within the myofibril during a single activation, several simulation models have been developed. These models follow a common pattern; divide the half sarcomere into a series of compartments, then use ordinary differential equations to solve reactions occurring within and between the compartments. To further develop this type of simulation, we have created a realistic structural model of a skeletal muscle myofibrillar half-sarcomere using MCell software that incorporates the myofilament lattice structure. Using this simulation model, we were successful in reproducing the averaged calcium transient during a single activation consistent with both the experimental and previous simulation results. In addition, our simulation demonstrated that the inclusion of the myofilament lattice within our model produced an asymmetric distribution of Ca2+, with more Ca2+ accumulating near the Z-disk and less Ca2+ reaching the m-line. This asymmetric distribution of Ca2+ is apparent when we examine how the Ca2+are bound to the troponin-c proteins along the actin filaments. Our simulation model also allowed us to produce advanced visualizations of this process, including two simulation animations, allowing us to view Ca2+ release, diffusion, binding and uptake within the myofibrillar half-sarcomere.
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    Three Dimensional Stochastic Computer Model of the Skeletal Muscle Half Sarcomere: changes in calcium diffusion caused by the myofilament lattice
    (2017) Holash, Robert John; MacIntosh, Brian; Chen, Wayne; Barclay, Chris; Jacob, Christian; ter Keurs, Henk
    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.
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    Validation of single maximal effort tests for power measurement
    (2000) Holash, Robert John; MacIntosh, Brian R.