Injury-Specific Muscle Regeneration: A Computational Blueprint for Cellular and Cytokine Drivers

Skeletal muscle regeneration is crucial for maintaining muscle health and mobility, making it a key research focus. Common experimental models of muscle injury used to study this process in vivo include cardiotoxin injury (CTX), freeze-induced (FI) injury, and eccentric contraction (EC) injury. While the response to injury varies across these models, these variations are often overlooked in experimental designs. The cellular dynamics throughout the time course of muscle regeneration differ significantly between these injury types, presenting challenges for both experimental investigation and literature analysis. To enhance understanding of how regeneration responses differ across injury types, we extend our previously validated computational model of skeletal muscle regeneration to simulate muscle fiber remodeling during regeneration following CTX, FI, and EC injuries. We further validate our model against multiple literature-derived metrics of regeneration for each injury type. Analysis of model outcomes reveals that recovery from each injury type is sensitive to unique combinations of cells and cytokines acting at different critical time points, exerting the greatest influence on regeneration at 28 days post-injury. Notably, the cytokines responsible for satellite cell (SSC) recruitment, proliferation, and differentiation required for regeneration vary across injury types, driven by biological redundancy and feedback mechanisms. Specifically, for EC injuries, cross-sectional area (CSA) recovery was predominantly associated with hepatocyte growth factor (HGF) and vascular endothelial growth factor A (VEGF-A) during the early stages of regeneration, with SSC dynamics playing a critical role throughout. FI injuries demonstrated a consistent reliance on HGF across all phases, with additional influences from transforming growth factor beta (TGF-{beta}), tumor necrosis factor-alpha (TNF-), monocyte chemoattractant protein-1 (MCP-1), and SSC dynamics in later stages. CTX injuries showed early dependence on TGF-{beta}, with significant contributions from SSC, TNF-, VEGF-A, and fibroblast dynamics over time. Our findings emphasize the importance of considering the molecular and cellular mechanisms relevant to each injury type used in pre-clinical in vivo studies, and motivates the development of therapeutic strategies that are designed for specific injury types to optimize recovery outcomes.