Twist1 protects intervertebral disc from degeneration via GLUT3 mediated glycolysis

BACKGROUND: The lack of a comprehensive understanding regarding the pathological mechanisms of intervertebral disc degeneration (IDD) impedes the development of effective therapeutic strategies. METHODS: Twist1 expression was evaluated in primary nucleus pulposus (NP) cells and clinical tissues. NP cell apoptosis and extracellular matrix (ECM) metabolism were detected to assess the impact of Twist1 on IDD, which was further demonstrated via in vivo assay. Glycolytic activity was estimated by measuring the extracellular acidification rate (ECAR), oxygen consumption rate (OCR), lactate production, and glucose consumption. Additionally, the intrinsic mechanisms by which Twist1 regulates glycolysis were thoroughly investigated through transcriptional study. RESULTS: Twist1 expression was significantly downregulated during IDD. Functional studies demonstrated that Twist1 mitigates IDD by suppressing NP cell apoptosis and maintaining ECM homeostasis. Crucially, this protective role was dependent on glycolysis, whose activity was markedly compromised during IDD. Mechanistically, Twist1 drives glycolytic flux through the direct transcriptional activation of the glucose transporter GLUT3 (SLC2A3). CONCLUSION: Twist1 protects the intervertebral disc from degeneration by promoting GLUT3-mediated glycolysis in NP cells, highlighting the Twist1-GLUT3-glycolysis axis as a promising therapeutic target for IDD.