Dual therapy maximizes nerve growth and functional recovery of muscle and bone

Research investigating neural regeneration has focused on restoring nerve-to-muscle connectivity, however the bone is a critical target of reinnervation that has been largely overlooked. Changes in bone mineral density (BMD) are associated with clinical neuropathies, and therapeutics that address the dual loss of both muscle function and skeletal integrity is a pressing, unmet need in the nerve injury patient population. In this study, the effects of integrating conditioning electrical stimulation (CES) with exercise rehabilitation using a tibial-to-peroneal distal nerve transfer (DNT) are evaluated. Sprague-Dawley rats underwent a right common peroneal crush to cause foot drop and were divided into four activity-dependent treatment groups: i) No Therapy (No Tx) in which the DNT was performed with no perioperative intervention, ii) CES, iii) exercise (EX), iv) CES+EX. Results show that CES+EX, compared to all other treatment groups, improves axonal regeneration, muscle and bone reinnervation, BMD, and spinal cord plasticity. Findings identify a synergistic relationship between these clinically feasible interventions that culminate into significantly improved locomotor mechanics and reduced secondary morbidity after nerve injury. By targeting both nerve regeneration and the musculoskeletal sequelae of nerve injury, we address the critical gap in understanding how the nervous system’s repair intertwines with muscle regeneration and skeletal health.