Rheb-regulated lactate metabolism in Schwann cells implicates in axonal regeneration after peripheral nerve injury

Peripheral nerve injuries are prevalent; however, the efficacy of its repairment is often suboptimal. Schwann cells, the principal glial cells in the peripheral nervous system, play a critical role in the process of axon regeneration following peripheral nerve injury. Nevertheless, their specific role and underlying mechanisms in this regenerative process remain inadequately understood. This study aims to investigate the influence of Rheb, a significant energy regulator in Schwann cells, on axonal regeneration following peripheral nerve injury, as well as to analyze the potential mechanisms involved. Immunostaining using anti-SCG10 was employed to assess the regeneration length in Schwann cell-specific Rheb knockout mice (Rheb cKO) after sciatic nerve crush injury. The regeneration length of neurites was compared among groups after the administration of lactic acid or equivalent amounts of glucose and lactate transporter inhibitors to primary cultured dorsal root ganglion (DRG) neurons. Western blot analysis was conducted to measure the levels of phosphorylated AKT (p-AKT) in Rheb cKO mice and cultured DRG neurons. The findings indicated that axonal regeneration was enhanced in Rheb cKO mice. Additionally, the content and release of lactate were significantly elevated in Rheb knockout Schwann cells. Treatment with lactate promoted longer neurite regeneration in cultured DRG neurons. Furthermore, the expression of p-AKT in Rheb cKO mice and lactate-treated DRG neurons was found to be increased. The ablation of Rheb in Schwann cells leads to increased lactate production, providing essential support to neurons. The lactate derived from Schwann cells participates in the axonal regeneration process by modulating the PI3K-AKT signaling pathway, functioning as an intracellular signaling molecule.