A mathematical model of healthy and dystrophic skeletal muscle biomechanics

Duchenne Muscular Dystrophy (DMD) is a common X-linked disease, caused by mutations in the gene encoding dystrophin and characterized by widespread muscle damage that invariably leads to paralysis and death. Lack of dystrophin in the muscles of DMD patients determines an increased fragility of muscle fibers, leading to repeated cycles of necrosis and regeneration that result in failed regeneration, increased fibrosis and progressive loss of muscle function. In this work, we propose a three-dimensional chemo-mechanical mathematical model of skeletal muscle in DMD. This model is based on stress-strain mechanical data of the muscle and studies of changes in fiber structure and interaction aiming to shade light into the biophysical mechanisms regulating muscle contraction. The results show that the model is able to reproduce the experimental data of maximum isometric force, maximum contraction velocity and concentric normalized F-V curve for the healthy and dystrophic muscle. Furthermore, the model is capable of predicting the force-velocity response of the muscle to eccentric loading without explicitly imposing its functional form in the formulation, and it is able to reproduce the concentric normalized F-V curve of the healthy fiber, as an additional proof of the predictive capabilities of the model. The resulting model represents a novel approach to study DMD pathogenesis by providing insights into the underlying mechanisms of muscle response to force associated with the impaired muscle functionality. Moreover, it could be an innovative tool for researchers to predict muscle response under conditions that are not possible to explore in the laboratory and an important step towards a new paradigm of in-silico trials that could allow identifying novel therapies bypassing the use of animal models. (C) 2019 Elsevier Ltd. All rights reserved.