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Duchenne muscular dystrophy is a progressive muscle wasting disease affecting 1 in 3500 boys. It is a recessive X-linked disease caused by a mutation in the dystrophin gene resulting in incomplete translation of the structural protein dystrophin that links the intracellular sarcomere to the extracellular matrix. Despite extensive research, there remains no cure for DMD. Cardiopulmonary failure, understood to be linked to diaphragm dysfunction, is the leading cause of mortality. The lack of this structural protein causes the dystrophic muscle to be highly susceptible to damage, leading to a state of chronic inflammation and replacement of contractile tissue with fibrotic tissue and fat. Understanding how these changes in the constituents of muscle tissue affect the in vivo function of the muscle is critical to developing therapies to improve the quality of life for boys with DMD. The goal of my dissertation is to couple benchtop experiments with computational modeling to elucidate the role of fibrotic tissue in diaphragm dysfunction. To accomplish this, we first measured the biaxial properties of healthy and dystrophic muscle tissue samples before and after enzymatic collagen digestion in order to isolate the effects of collagen on passive tissue mechanics. Our measurements revealed significant correlations between collagen quantity and both along and across fiber stiffness We then measured the in vivo mechanics of healthy and dystrophic diaphragms through a novel sonomicrometry method in order to examine how muscular dystrophy impacts the in vivo active mechanics. Measurements of in vivo diaphragm contraction revealed a significant decrease in strains and strain rates associated with disease state. When considering the effects of fibrosis, we found a significant correlation between collagen quantity and measured strains. Finally, we integrated our experiments to develop and validate finite-element models of the both healthy and dystrophic diaphragms. Using these models, we performed “what-if” simulations to illuminate how restoring either the active or passive mechanics of dystrophic muscle would impact diaphragm function. The modeling analysis predicted a 75% recovery with restoration of the force production capabilities of healthy muscle and a 35% recovery by changing the passive properties. These results highlight the need to consider both restoration of active properties and the regulation of fibrosis when developing therapies. Further development of the experimental methods and model in this dissertation could provide additional testing metrics for drug therapies as well as identify targets for new therapies. |
