Electrical stimulation promotes peripheral nerve regeneration by upregulating glycolysis and oxidative phosphorylation

Abstract

Peripheral nerve injury (PNI) frequently results in motor and sensory dysfunction due to the limited regenerative capacity of axonal neurons and Schwann cells. Electrical stimulation (ES) has emerged as a promising strategy to enhance nerve regeneration; however, the underlying mechanisms, particularly those related to energy metabolism, remain poorly understood. This study aimed to investigate whether ES could promote nerve regeneration in a mouse model of PNI by modulating energy metabolism. ES was applied to the gastrocnemius and posterior thigh muscles post-sciatic nerve injury. Motor functional recovery was evaluated using gait analysis and electrophysiological test. Molecular and cellular changes in the distal nerve stumps were evaluated through Western blot and immunofluorescence staining. Nerve regeneration was assessed by neurostructural protein staining and nerve ultrastructure visualized by transmission electron microscopy. Our findings indicate that ES significantly accelerated both morphological and functional recovery following PNI. Specifically, ES upregulated energy metabolism in the sciatic nerve post-PNI by enhancing glucose uptake, glycolysis, and oxidative phosphorylation. Furthermore, ES increased the expression of neurotrophic factors and modulated the AMPK/mTOR/p70S6K signaling pathway, which are crucial for cellular metabolism and nerve regeneration. Collectively, these findings underscore the critical role of ES in modulating energy metabolism to support nerve regeneration, highlighting its potential as a clinical strategy for treating peripheral neuropathy.