Abstract
Traumatic musculoskeletal injuries that lead to volumetric muscle loss (VML) are challenged by irreparable soft tissue damage, impaired regenerative ability, and reduced muscle function. Regenerative rehabilitation strategies involving the pairing of engineered therapeutics with exercise have guided considerable advances in the functional repair of skeletal muscle following VML. However, few studies evaluate the efficacy of regenerative rehabilitation across the lifespan. In the current study, young and aged mice are treated with an engineered muscle, consisting of nanofibrillar-aligned collagen laden with myogenic cells, in combination with voluntary running activity following a VML injury. Overall, young mice perform at higher running volumes and intensities compared to aged mice but exhibit similar volumes relative to age-matched baselines. Additionally, young mice are highly responsive to the dual treatment showing enhanced force production (p < 0.001), muscle mass (p < 0.05), and vascular density (p < 0.01) compared to age-matched controls. Aged mice display upregulation of circulating inflammatory cytokines and show no significant regenerative response to treatment, suggesting a diminished efficacy of regenerative rehabilitation in aged populations. These findings highlight the restorative potential of regenerative engineering and rehabilitation for the treatment of traumatic musculoskeletal injuries in young populations and the complimentary need for age-specific interventions and studies to serve broader patient demographics.