Auckland Bioengineering Institute, The University of Auckland, Auckland, New Zealand.
Department of Engineering Science, The University of Auckland, Auckland, New Zealand.
PLoS Comput Biol. 2023 Apr 6;19(4):e1011042. doi: 10.1371/journal.pcbi.1011042. eCollection 2023 Apr.
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.
健康的骨骼肌在运动等活动中会对机械性局部应变做出修复反应。细胞将外部刺激转化为细胞信号反应级联的能力对于肌肉修复和再生过程非常重要。在慢性肌病（如杜氏肌营养不良症和炎性肌病）中，肌肉经常受到慢性坏死和炎症的影响，这会破坏组织内稳态，并导致组织内非局部、广泛的损伤。在这里，我们提出了一个基于代理的模型，该模型模拟了肌肉对局部离心收缩（类似于运动时所经历的）和慢性疾病中存在的非局部广泛炎症损伤的修复反应。肌肉修复的计算建模允许对与肌肉疾病相关的现象进行计算机模拟探索。在我们的模型中，广泛的炎症导致组织损伤的清除延迟，并且在所有损伤水平下初始原纤维计数的修复恢复也延迟。与局部损伤相比，广泛损伤导致巨噬细胞募集延迟且数量明显更高。在损伤百分比更高的 10%时，广泛损伤会导致肌肉再生受损以及肌肉几何形状发生变化，这代表了慢性肌病中常见的改变，如纤维化。这项计算工作深入了解了炎症性肌肉疾病的进展和发病机制，并提示关注肌肉再生级联反应，以了解炎症性肌病中肌肉损伤的进展。
