A Coupled Mechanobiological Model of Muscle Regeneration In Cerebral Palsy

Abstract

Cerebral palsy is a neuromusculoskeletal disorder associated with muscle weakness, altered muscle architecture, and progressive musculoskeletal symptoms that worsen with age. Pathological changes at the level of the whole muscle have been shown; however, it is unclear why this progression of muscle impairment occurs at the cellular level. The process of muscle regeneration is complex, and the interactions between cells in the muscle milieu should be considered in the context of cerebral palsy. In this work, we built a coupled mechanobiological model of muscle damage and regeneration to explore the process of muscle regeneration in typical and cerebral palsy conditions, and whether a reduced number of satellite cells in the cerebral palsy muscle environment could cause the muscle regeneration cycle to lead to progressive degeneration of muscle. The coupled model consisted of a finite element model of a muscle fiber bundle undergoing eccentric contraction, and an agent-based model of muscle regeneration incorporating satellite cells, inflammatory cells, muscle fibers, extracellular matrix, fibroblasts, and secreted cytokines. Our coupled model simulated damage from eccentric contraction followed by 28 days of regeneration within the muscle. We simulated cyclic damage and regeneration for both cerebral palsy and typically developing muscle milieus. Here we show the nonlinear effects of altered satellite cell numbers on muscle regeneration, where muscle repair is relatively insensitive to satellite cell concentration above a threshold, but relatively sensitive below that threshold. With the coupled model, we show that the fiber bundle geometry undergoes atrophy and fibrosis with too few satellite cells and excess extracellular matrix, representative of the progression of cerebral palsy in muscle. This work uses in silico modeling to demonstrate how muscle degeneration in cerebral palsy may arise from the process of cellular regeneration and a reduced number of satellite cells.

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

“…These agents were not prescribed a speed and instead moved to damage locations once per time step, and it was assumed that they could move across more than a single pixel length within the hour. Macrophage and neutrophil numbers have been compared to literature values in Khuu et al [ 5 ], where days post injury for peak amplitude of cell counts was consistent with existing studies. Objects that were phagocytosed included ECM and fibrils.…”

“…The ABM was developed in Repast Simphony [ 42 ], a Java-based modelling toolkit, and expands on ABM previously described in Khuu et al [ 5 ]. ABM geometry was based on pixel geometry of a histological slice from the literature [ 39 ] (see aforementioned description).…”

“…Each simulation was run 50 times, and simulation results are shown as mean ± standard deviation (SD). The ABM framework is based on [ 5 ] with changes to fibre geometry, input strain thresholds to match the current FEM strain values, fibroblast cell migration, SC movement to repair the next nearest damaged neighbour, and cytokine and growth factor expression coefficients determined using an optimisation algorithm (see subsection Genetic Algorithm). The complete model code, portable archive file, and instructions (readme file) for running the model can be found at https://github.com/stkhuu/muscleRegen.git .…”

“…In ABM, dynamic interactions reflect the complex and nonlinear nature of physiological systems, and often lead to emergent phenomena. Previously ABM has been used to explore disuse induced atrophy [ 3 ], the Duchenne muscular dystrophy (DMD) muscle microenvironment [ 4 ], and the muscle repair process in cerebral palsy [ 5 ].…”

Muscle architecture, growth, and biological Remodelling in cerebral palsy: a narrative review

“…While impaired muscular development has been observed at around 15 months of age, atypical movements are noticeable as early as 3 months of age [170], potentially implying that muscle morphology is a downstream effect of altered neural activation and biomechanics, rather than a direct consequence of the neural lesion. Separating these issues in a reductive approach is difficult, but advancements in computational modelling and bioengineering approaches [171,172] create new advanced possibilities for simulating and understanding these mechanisms.…”