Mechanobiological Modelling of Human Skeletal Muscle Regeneration in Healthy and Pathological Conditions

Abstract

Healthy skeletal muscle is a robust tissue that adapts with use. Muscle contraction— especially eccentric or active lengthening contraction— that occurs during exercise, causes damage to muscle fibre membranes and triggers a signalling cascade within the muscle fibre environment. The repair of this damage over time leads to advantageous adaptations such as muscle growth and hypertrophy in healthy muscle; however, little is known about the changes to the repair process that occur in chronic muscle diseases such as cerebral palsy, Duchenne muscular dystrophy, and inflammatory myopathies. Restoring muscle growth, strength, and regenerative potential in pathological muscle would be the holy grail of treatment for myopathies. Skeletal muscle homeostasis is maintained by cells in the muscle environment. Satellite cells (SC) are a muscle resident progenitor cell population, and the SC niche regulates regenerative potential. Attempts to replenish SCs in ageing or pathological tissue have illustrated the system’s complexity and the inability of SCs to independently repair muscle. The activity of neutrophils, macrophages, muscle cells and fibroblasts are essential in regulating muscle repair. The interactions of these cells and their chemical environment ultimately lead to changes to the whole muscle. Agent-based modelling (ABM) is a bottom-up computational modelling framework where individual agents are programmed with sets of rules that they follow, responding to their environment and other agents in a bottom-up fashion. ABM is a valuable tool in connecting multiple scales of muscle physiology. Coupling ABM with mechanical strain from finite element (FE) modelling of muscle provides an avenue to investigate physiological changes in muscle over time. This thesis presents coupled models of skeletal muscle repair in healthy and pathological conditions that evaluates stages of muscle repair and how they contribute to the muscle regeneration system as a whole, without a priori macro-scale assumptions. The coupled agent-based model was used to evaluate the repair process following changes in the cell environment of healthy and pathological muscle fibre bundles in response to changes in the mode of damage and changes to regenerative potential. Regulation of the muscle repair system at the cellular level is crucial to macro-scale muscle function and morphology. These models highlight the importance of understanding the muscle milieu in detail so as to maintain and restore regenerative potential. Understanding the interactions between cells and their regulation by the environment using coupled ABMs of muscle repair is a promising technique to test and discover more targeted hypotheses that lead to therapeutic pathways for muscle repair.