Delayed skeletal muscle repair following inflammatory damage in simulated agent-based models of muscle regeneration

Author summarySkeletal muscles are robust tissues that allow individuals to move and perform daily activities. Healthy muscle can repair following exercise and injury within 2-4 weeks, depending on severity. The damage to skeletal muscle following exercise is typically localised to areas along muscle fibres; however, in muscles affected by Duchenne Muscular Dystrophy and inflammatory myopathies, the damage to muscle tissue is more widespread. Little is known about how the localisation of injury in muscle affects the response of cells and chemicals involved in the repair process. Here, we built a computational model of human skeletal muscle repair following both localised (typical) and widespread (inflammatory) injury to explore the effect of injury localisation on repair time and cell numbers. Simulations of widespread damage similar to that found in pathological scenarios led to delayed clearance of damaged tissue and delayed repair of the initial fibril number. These changes led to morphological changes in muscle geometry and reflected commonly observed changes in pathological muscle. Healthy skeletal muscle undergoes repair in response to mechanically localised strains during activities such as exercise. The ability of cells to transduce the external stimuli into a cascade of cell signalling responses is important to the process of muscle repair and regeneration. In chronic myopathies such as Duchenne muscular dystrophy and inflammatory myopathies, muscle is often subject to chronic necrosis and inflammation that perturbs tissue homeostasis and leads to non-localised, widespread damage across the tissue. Here we present an agent-based model that simulates muscle repair in response to both localised eccentric contractions similar to what would be experienced during exercise, and non-localised widespread inflammatory damage that is present in chronic disease. Computational modelling of muscle repair allows for in silico exploration of phenomena related to muscle disease. In our model, widespread inflammation led to delayed clearance of tissue damage, and delayed repair for recovery of initial fibril counts at all damage levels. Macrophage recruitment was delayed and significantly higher in widespread compared to localised damage. At higher damage percentages of 10%, widespread damage led to impaired muscle regeneration and changes in muscle geometry that represented alterations commonly observed in chronic myopathies, such as fibrosis. This computational work offers insight into the progression and aetiology of inflammatory muscle diseases, and suggests a focus on the muscle regeneration cascade in understanding the progression of muscle damage in inflammatory myopathies.