Glutamine suppresses senescence and promotes autophagy through glycolysis inhibition-mediated AMPK lactylation in intervertebral disc degeneration

Regulating metabolic disorders has become a promising focus in treating intervertebral disc degeneration (IDD). A few drugs regulating metabolism, such as atorvastatin, metformin, and melatonin, show positive effects in treating IDD. Glutamine participates in multiple metabolic processes, including glutaminolysis and glycolysis; however, its impact on IDD is unclear. The current study reveals that glutamine levels are decreased in severely degenerated human nucleus pulposus (NP) tissues and aging Sprague-Dawley (SD) rat nucleus pulposus tissues, while lactate accumulation and lactylation are increased. Supplementary glutamine suppresses glycolysis and reduces lactate production, which downregulates adenosine-5'-monophosphate-activated protein kinase alpha (AMPK alpha) lactylation and upregulates AMPK alpha phosphorylation. Moreover, glutamine treatment reduces NP cell senescence and enhances autophagy and matrix synthesis via inhibition of glycolysis and AMPK lactylation, and glycolysis inhibition suppresses lactylation. Our results indicate that glutamine could prevent IDD by glycolysis inhibition-decreased AMPK alpha lactylation, which promotes autophagy and suppresses NP cell senescence. Glutamine could prevent IDD by glycolysis inhibition through decreased AMPK alpha lactylation, which promotes autophagy and suppresses NP cell senescence.