LDHA-Mediated Glycolytic Metabolism in Nucleus Pulposus Cells Is a Potential Therapeutic Target for Intervertebral Disc Degeneration

Abstract

The intervertebral disc degeneration (IDD) is considered to be an initiator of a series of spinal diseases, among which changes in the nucleus pulposus (NP) are the most significant. NP cells reside in a microenvironment with a lack of blood vessels, hypoxia, and low glucose within the intervertebral disc. Due to the strong activity of HIF-1α, glycolysis is the main pathway for energy metabolism in NP cells. Our previous study found that higher SIRT1 expression is beneficial to delay the degeneration of NP cells. In order to find the downstream genes by which SIRT1 acts on NP cells, we used iTRAQ sequencing to detect the differences between degenerated NP cells overexpressing SIRT1 and a control group (human NP cells were derived from surgery) and found that the expression of LDHA changed in the same direction with SIRT1. This suggests that SIRT1 may delay the degeneration of NP cells by regulating glycolysis. We then used a Seahorse XFe24 analyzer to measure the bioenergetic parameters of NP cells and obtained three findings: (a) glycolysis is the main energy metabolism pathway in NP cells, (b) there is a large difference in ATP production between senescent cells and young cells, and (c) SIRT1 can regulate the production of ATP from glycolysis by regulating LDHA. We also found that SIRT1 in NP cells has a positive regulatory effect on c-Myc which is an upstream gene of LDHA. Through observing IDD-related indicators such as apoptosis, proliferation, senescence, and extracellular matrix, we found that SIRT1 can delay degeneration, and interference with c-Myc and LDHA, respectively, weakens the protective effect of SIRT1. Interfering with LDHA alone can also inhibit glycolysis and accelerate degeneration. Overall, we found that the inhibition of glycolysis in Np cells significantly affects their normal physiological functions and determined that LDHA is a potential therapeutic target for the treatment of IDD.

Emerging role and therapeutic implication of mTOR signalling in intervertebral disc degeneration

“…[129][130][131] In IDD, glycolysis is the main pathway of energy metabolism in NP cells, and inhibition of glycolysis in NP cells can significantly impact their normal physiological functions. 132 Inhibition of pyroptosis or ferroptosis was found to delay IDD progression. 133,134 Furthermore, the functions of the mTOR signalling pathway in glycolysis, pyroptosis, and…”

“…Moreover, the mTOR signalling pathway is known to be involved in glycolysis, pyroptosis, and ferroptosis in various diseases 129–131 . In IDD, glycolysis is the main pathway of energy metabolism in NP cells, and inhibition of glycolysis in NP cells can significantly impact their normal physiological functions 132 . Inhibition of pyroptosis or ferroptosis was found to delay IDD progression 133,134 .…”

Cellular Senescence in Intervertebral Disc Aging and Degeneration: Molecular Mechanisms and Potential Therapeutic Opportunities

“…As a metabolic/nutrient sensor, SIRT1 is localized in the nucleus but can shuttle between the nucleus and cytoplasm under specific conditions [ 99 ]. It is highly expressed in healthy human discs but its level decreases in degenerated discs [ 100 ]. In degenerated discs, reduced SIRT1 expression leads to inhibition of c-Myc mediated lactate dehydrogenase A (LDHA) expression, resulting in reduced glycolysis pathway and ultimately increased CS [ 100 ].…”

“…It is highly expressed in healthy human discs but its level decreases in degenerated discs [ 100 ]. In degenerated discs, reduced SIRT1 expression leads to inhibition of c-Myc mediated lactate dehydrogenase A (LDHA) expression, resulting in reduced glycolysis pathway and ultimately increased CS [ 100 ]. Oxidative stress increases phosphorylation of forkhead box protein O1 (FOXO1), decreasing its nuclear translocation and inhibits the SIRT1 pathway via activating the Akt [ 101 ].…”

Advanced glycation end products induce nucleus pulposus cell apoptosis by upregulating TXNIP via inhibiting glycolysis pathway in intervertebral disc degeneration

“…Glycolysis is the main energy metabolism pathway in NP cells. [ 14 ] To date, two glucose transporter families have been identified, including the main GLUT superfamily (GLUTs) and the sodium‐glucose co‐transporter SGLT family (SGLTs). [ 15 ] As members of the GLUTs, GLUT1 and GLUT4 are important glucose transporter proteins responsible for glucose uptake across the plasma membrane.…”