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.

中文翻译：

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脑瘫肌肉再生的耦合机械生物学模型。

脑瘫是一种神经肌肉骨骼疾病，与肌肉无力、肌肉结构改变以及随着年龄的增长而恶化的进行性肌肉骨骼症状有关。已显示出整个肌肉水平的病理变化；然而，目前尚不清楚为什么这种肌肉损伤的进展发生在细胞水平上。肌肉再生的过程很复杂，在脑瘫的背景下应考虑肌肉环境中细胞之间的相互作用。在这项工作中，我们建立了肌肉损伤和再生的耦合力学生物学模型，以探索典型和脑瘫条件下的肌肉再生过程，以及脑瘫肌肉环境中卫星细胞数量的减少是否会导致肌肉再生周期导致肌肉进行性退化。耦合模型由经历偏心收缩的肌纤维束的有限元模型和基于代理的肌肉再生模型组成，该模型包含卫星细胞、炎症细胞、肌纤维、细胞外基质、成纤维细胞和分泌的细胞因子。我们的耦合模型模拟了偏心收缩造成的损伤，以及随后 28 天的肌肉再生。我们模拟了脑瘫和典型发育肌肉环境的循环损伤和再生。在这里，我们展示了卫星细胞数量改变对肌肉再生的非线性影响，其中肌肉修复对高于阈值的卫星细胞浓度相对不敏感，但低于该阈值则相对敏感。通过耦合模型，我们发现纤维束几何形状发生萎缩和纤维化，卫星细胞太少，细胞外基质过多，代表肌肉中脑瘫的进展。这项工作使用计算机模型来证明脑瘫中的肌肉退化是如何由细胞再生过程和卫星细胞数量减少引起的。