A Coupled Mechanobiological Model of Muscle Regeneration In Cerebral Palsy

Stephanie Khuu,Justin W Fernandez,Geoffrey G Handsfield

doi:10.3389/fbioe.2021.689714

Stephanie Khuu, Justin W Fernandez + Show 1 more

Open Access

https://doi.org/10.3389/fbioe.2021.689714

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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.

Highlights

Cerebral palsy (CP) is a neuromusculoskeletal disorder arising from a static neural lesion but leading to musculoskeletal and gait impairments that can give rise to long-term degradation of musculature (Fridén and Lieber, 2003; Smith et al, 2011; Larkin-Kaiser et al, 2019)
Of the few recent studies performed on CP muscle, cellular level differences between CP and typically developing (TD) muscle have been found and include increased collagen deposition in the extracellular matrix (ECM) (Booth et al, 2001; Fridén and Lieber, 2003; De Bruin et al, 2014), decreased number of muscle stem cells (Smith et al, 2013), decreased stem cell activity (Domenighetti et al, 2018), and an increase in proinflammatory gene expression compared to TD muscle (Von Walden et al, 2018)
The muscle fiber environment undergoes a tightly regulated adaptive repair process which is often categorized according to a series of four phases of regeneration: 1) damage in the form of membrane rupture, 2) acute inflammatory response from macrophages and neutrophils, which involves breakdown and clearance of necrotic tissue, 3) regeneration orchestrated by activation, proliferation, differentiation of myogenic precursor cells and fusion of myoblasts to the debrided region of the myofiber, and 4) repair and remodeling of the ECM by fibroblasts (Partridge, 2002; Mourkioti and Rosenthal, 2005; Chargé and Rudnicki, 2009; Novak et al, 2014; Laumonier and Menetrey, 2016)

Summary

Introduction

Cerebral palsy (CP) is a neuromusculoskeletal disorder arising from a static neural lesion but leading to musculoskeletal and gait impairments that can give rise to long-term degradation of musculature (Fridén and Lieber, 2003; Smith et al, 2011; Larkin-Kaiser et al, 2019). Eccentric exercise stimulation of muscles attenuates age-related muscle loss and promotes myofiber hypertrophy (Chen et al, 2020) Stimuli such as eccentric lengthening exercises cause mechanical strains in the muscle that damage cell membranes and lead to a cascade of chemical signals and cellular responses. Macrophages phagocytose cellular debris and activate myogenic cells, ready for the regeneration process (Novak et al, 2014) Their importance in skeletal muscle regeneration is due to their phagocytic and antigen-presenting roles (Tidball and Villalta, 2010). Arnold et al, 2007 postulate that phagocytosis of muscle cell debris induces a switch of proinflammatory macrophages toward an anti-inflammatory phenotype, releasing TGF-β This suggests that inflammatory macrophages stimulate myogenic proliferation while anti-inflammatory macrophages exhibit differentiating activity

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