Duchenne muscular dystrophy is a devastating neuromuscular disease affecting 1 in 3500 boys, leading to severe muscle wasting and accumulation of extracellular matrix (ECM) components during fibrosis. Despite extensive experimental research there remains no effective treatment for this fatal disease and respiratory insufficiency is a leading cause of death. Fibrosis contributes to muscle dysfunction but the structure and function of fibrotic tissue are largely uncharacterized. In this project we are interested in how the organization of collagen, the key contributor to the tensile properties of the skeletal muscle ECM, influences diaphragm muscle function during fibrosis.

At the ECM-level, we use imaging methods such as scanning electron microscopy (SEM) to visualize collagen structure and develop finite-element models to determine the mechanical implications of changes in collagen structure during fibrosis. At the muscle-level, we develop finite-element models to understand the complex effects of fibrotic tissue structure on damage susceptibility and muscle tissue mechanics. Then we can couple these models with agent-based models to study the progression of fibrosis in dystrophic muscle, particularly the relationships between ECM mechanics and dynamic cellular behaviors during fibrosis.

MODELING CELLULAR BEHAVIORS DURING MUSCLE REGENERATION 

Computational models are an ideal complement to experimental efforts for understanding complex phenomena such as muscle degeneration, regeneration, and remodeling, which emerge from the dynamic behaviors and interactions of individual, heterogeneous cells that are mediated by numerous biochemical signals. While our fundamental understanding of the individual cellular and subcellular behaviors of muscle cells has advanced, there remain no effective treatment methods to accelerate muscle regeneration and reduce fibrosis. In our lab, we use agent-based modeling to study the impact of cell behaviors, cytokine expression, and sex hormones on muscle regeneration. These models are used to test variations of growth factor levels to develop optimized treatments for muscle regeneration that account for variations in estrogen levels.