Lactate Promotes Nucleus Pulposus Cell Senescence, Oxidative Stress, and Corresponding Intervertebral Disc Degeneration

Abstract

Abstract The accumulation of metabolites in the intervertebral disc is considered to be an important cause of intervertebral disc degeneration (IVDD). Lactate, which is a metabolite that is produced by cellular anaerobic glycolysis, has been proven to be closely associated with IVDD. However, little is known about the role of lactate in nucleus pulposus cell (NPC) senescence and oxidative stress. This study attempted to investigate the effect of lactate on NPC senescence and oxidative stress as well as the underlying mechanism. A puncture-induced disc degeneration (PIDD) model was established in rats. Metabolomics analysis proved that lactate levels were significantly increased in the degenerated intervertebral discs. Elimination of excessive lactate levels using lactate oxidase (LOx)-overexpressing lentivirus alleviated the progression of IVDD. In vitro experiments showed that high concentrations of lactate could induce senescence and oxidative stress in NPC. High-throughput RNA sequencing results and bioinformatic analysis demonstrated that the induction of NPC senescence and oxidative stress by lactate may be related to the PI3K/Akt signalling pathway. Further study verified that high concentrations of lactate could induce NPC senescence and oxidative stress by inhibiting PI3K/Akt signalling and the downstream Akt/p21/p27/cyclin D1 and Akt/Nrf2/HO-1 pathways. Utilizing molecular docking and microscale thermophoresis assay, we found that lactate could suppress Akt phosphoactivation by binding to the Lys39 and Leu52 residues in the PH domain of Akt. These results highlight the involvement of lactate in NPC senescence and oxidative stress, and lactate may become a novel potential therapeutic target for the treatment of IVDD.