Targeting the central–peripheral–effector muscle axis: Rapamycin promotes functional recovery in injured peripheral nerves

Peripheral nerve repair requires not only axonal regeneration and remyelination but also preservation of spinal circuitry and denervated target muscles during the denervation and regenerative period. We investigated whether Rapamycin treatment could improve repair across the central–peripheral–effector muscle axis after sciatic nerve crush injury. Mice were assigned to sham, crush, 3-methyladenine, or rapamycin groups and evaluated using histological, ultrastructural, molecular, transcriptomic, electrophysiological, and behavioral analyses, together with injury-conditioned dorsal root ganglion cultures and RSC96 Schwann cell assays. Rapamycin accelerated axonal extension, enhanced axon maturation and remyelination, improved myelin ultrastructure, and promoted Schwann cell proliferation, migration, and neurite outgrowth. In the spinal cord, rapamycin reduced neuronal apoptosis and glial activation, preserved synaptic markers, and was associated with transcriptional changes involving inflammatory, extracellular matrix remodeling, nociceptive, synaptic, axonal growth, and myelination-related programs. In denervated gastrocnemius muscle, Rapamycin preserved muscle mass and myofiber area, reduced ubiquitin-associated protein degradation, and increased neuromuscular junction reinnervation. These effects were accompanied by changes in autophagy-related markers, including an increased LC3-II/LC3-I ratio and reduced p62 expression, together with altered mTORC1, AMPK, and AKT signaling. Rapamycin further improved sensory reinnervation, compound muscle action potential amplitude, gait, and motor and sensory recovery. These findings indicate that Rapamycin promotes peripheral nerve repair through multi-level protective effects involving regenerating axons, spinal neural circuitry, and denervated muscle.