Development of an Agent-Based Model to Investigate Long-term Disease Progression in Duchenne Muscular Dystrophy

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Crump, Katherine, Biomedical Engineering - School of Engineering and Applied Science, University of Virginia
Crump, Katherine, Engineering Graduate, University of Virginia

Duchenne muscular dystrophy (DMD) is a severe muscle wasting disease that affects 1 in every 3,500 boys. Patients with DMD require a wheelchair by age 12, and ultimately die due to respiratory or cardiac failure by the mid 20s. The initiating cause of DMD is known – the absence of dystrophin, a protein that associates with a multimolecular network of integral and subsarcolemmal proteins, known as the dystrophin glycoprotein complex (DGC). Dystrophin and the DGC form a physical link between the intracellular cytoskeleton of the muscle fiber and the extracellular matrix. Without dystrophin, the DGC fails to properly form at the sarcolemma and the link is compromised, which diminishes the strength of the muscle fiber membrane. The weak membrane is susceptible to damage by muscle contractions during everyday movements, which can initiate a cascade of muscle fiber necrosis, chronic inflammation, and ultimately progressing to severe muscle weakness. However, despite extensive research and knowing the cause of DMD, there is no cure for DMD and current treatments have had limited efficacy because promising treatments in mice do not translate to clinical benefit in patients. Treatment is difficult because DMD and muscle regeneration are complex processes, involving mechanisms that transcend spatial and temporal scales.
Computational modeling provides a powerful to tool to investigate complex behaviors in skeletal muscle that may not be accessible through experiments due to cost or limitations in equipment. In this thesis, I present a computational model of chronic muscle degeneration in the mdx mouse. Through modifications to an acute injury model of DMD published by Virgilio et al., the new model presented here combines the strengths of other previously developed computational models (Martin et al., Jarrah et al., and Houston et al.) to offer a more comprehensive simulation of repetitive injury, cellular interactions, inflammatory cues, and muscle repair. New dystrophic conditions were defined by literature-derived rules and various damage protocols were tested to produce a model of disease progression in the mdx mouse that is validated by published literature data on change in fibrosis, satellite stem cell count, and macrophage cell count. Through low-level, daily injuries, the model simulations capture the peak damage before the mdx mouse is 3 months old and the switch from a pro-inflammatory environment to an anti-inflammatory, pro-fibrotic environment after 6 months.

MS (Master of Science)
agent-based model, Duchenne muscular dystrophy, skeletal muscle, fibrosis
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