Injury-specific muscle regeneration: a computational blueprint for cellular and cytokine drivers

Skeletal muscle regeneration is essential for maintaining muscle health and mobility, making it a key area of research. Common in vivo injury models include cardiotoxin (CTX), freeze-induced (FI) and eccentric contraction (EC) injuries. Despite clear differences in regeneration responses, these variations are often overlooked in experimental design. To address this, we extend a validated computational model to simulate muscle fibre remodelling after CTX, FI and EC injuries and further validate it using literature-derived regeneration metrics. Our analysis reveals that each injury type triggers unique cellular and cytokine interactions that influence regeneration, particularly around 28 days post-injury. EC injury recovery is mainly driven by hepatocyte growth factor (HGF), vascular endothelial growth factor A (VEGF-A) and satellite stem cell (SSC) activity in early stages. FI injuries consistently rely on HGF throughout, with transforming growth factor-β (TGF-β), tumour necrosis factor-α (TNF-α), monocyte chemoattractant protein-1 (MCP-1) and SSCs contributing in later phases. CTX injuries show early TGF-β influence and later roles for SSCs, TNF-α, VEGF-A and fibroblast dynamics. These findings reveal distinct regeneration trajectories across injury models that differ in both mode and severity, highlighting potential molecular and cellular mechanisms that warrant further investigation. Our validated model provides a computational framework for future systematic exploration of how injury severity and other initial conditions independently influence regeneration outcomes, which could inform tailored therapeutic strategies in preclinical studies.