Cytokine Gene Polymorphisms, Immune-Mediated Inflammatory Pathways, and Molecular Regulation of Tissue Repair Following Exercise-Induced Muscle Injury

Exercise-induced muscle injury (EIMI) is a common consequence of strenuous or unaccustomed physical activity and is frequently associated with delayed onset muscle soreness, transient strength loss, and reduced functional capacity. Although often reversible and adaptive, EIMI involves a complex interplay of mechanical disruption, inflammatory signaling, and regenerative processes. Structural damage to myofibers induces calcium dysregulation, sarcomere disruption, and proteolytic activation, resulting in the release of damage-associated molecular patterns that stimulate innate and adaptive immune responses. Neutrophils and macrophages coordinate debris clearance and inflammatory signaling, while the transition from pro-inflammatory to anti-inflammatory macrophage phenotypes is important for effective tissue repair. Cytokines and chemokines tightly regulate these responses, as excessive or prolonged inflammation may promote fibrosis and delayed recovery. Genetic variability, particularly cytokine gene polymorphisms, contributes to inter-individual differences in inflammatory magnitude, recovery kinetics, and susceptibility to muscle damage. Variants in IL-6, TNF-α, IL-1β, IL-10, and chemokine genes influence cytokine expression, macrophage polarization, and satellite cell activity. Key pathways including NF-κB and JAK/STAT signaling, reactive oxygen species production, growth factor regulation, extracellular matrix remodeling, and epigenetic mechanisms further shape muscle regeneration. Current evidence underscores the importance of integrating immunological and genetic insights to better understand muscle repair. Future research focusing on multi-ethnic cohorts, polygenic models, and single-cell and epigenetic profiling may enhance translational applications. Advancing knowledge in this field may support personalized exercise medicine, targeted therapeutic strategies, and improved management of muscle recovery.