Cellular signaling within aged skeletal muscle reveals a dysregulated stress-induced remodeling response following volumetric muscle loss in female mice.

Severe muscle trauma disrupts endogenous repair mechanisms and produces chronic functional deficits that are poorly defined in aging. We investigated inflammatory, molecular, and physiological responses to volumetric muscle loss in young adult and aged female mice. Cytokine profiling revealed elevated baseline inflammation in aged mice and a blunted early injury response; for example, IL-6 increased 4.4-fold in young versus 1.8-fold in aged mice at day 3 post-injury. By day 28, histological analyses revealed comparable reductions in muscle size and increased fibrosis across ages. Despite similar structural pathology, age-dependent differences emerged in functional and molecular adaptations. Both groups exhibited persistent force deficits; however, aged muscles showed significantly altered relaxation kinetics (p < 0.001), suggesting dysregulated excitation-contraction coupling. Aged mice also demonstrated altered post-injury limb loading patterns. Global proteomics identified age-associated enrichment of complement and antigen-processing pathways and signatures of metabolic dysfunction (p < 0.05). Phosphoproteomic analysis revealed reduced basal kinase activity in aged muscle but exaggerated injury-induced phosphorylation of Mapk1-associated sites indicating a dysregulated stress response. Together, these findings indicate that aging muscles operate within a heightened inflammatory and perturbed kinase-signaling environment that may impair coordinated regeneration and functional recovery following traumatic injury.