MCT1-Mediated Endothelial Cell Lactate Shuttle as a Target for Promoting Axon Regeneration after Spinal Cord Injury

Abstract Vascular damage following spinal cord injury (SCI) precipitates ischemia and hypoxia at the injury site, leading to profound metabolic disturbances. The implications of these metabolic disorders on neural tissue remodeling and functional recovery remain poorly understood. Our study elucidates the consequences of the hypoxic environment induced by SCI, which significantly enhances glycolysis and lactate production at the injury's epicenter. And our findings revealed a marked decrease in the expression of Monocarboxylate Transporter 1 (MCT1), a crucial transporter facilitating lactate delivery to neurons and consequently supporting their energy metabolism, within vascular endothelial cells emerging after SCI. This decrease disrupts lactate transport to neurons, resulting in metabolic imbalances that impede axonal regeneration. Remarkably, our research demonstrates that targeted delivery of adeno-associated virus (AAV) injections to restore MCT1 expression in endothelial cells (ECs) promotes axonal regeneration and functional recovery in SCI mouse models. These findings reveal a previously unrecognized connection between lactate shuttling from ECs to neurons after SCI and neural functional recovery. Highlighting a novel metabolic pathway for intervention, our study opens new therapeutic avenues for the treatment of spinal cord injuries, suggesting that targeting lactate transport mechanisms may offer significant benefits in SCI recovery.