Loss of MCT1 mediated lactate uptake causes delayed endplate maturation and intervertebral disc degeneration
Abstract
During skeletal growth, it is thought that the lactate secreted by the glycolytic nucleus pulposus (NP) cells exits the intervertebral disc into circulation via endplates. Our current studies challenge this long-held notion. Mice with early postnatal, endplate, and annulus fibrosus-specific deletion of lactate importer, MCT1, exhibited disc degeneration characterized by NP cell loss and pronounced endplate structural changes. Using metabolic and transcriptomic approaches, we demonstrate that MCT1 loss inhibits endplate chondrocyte differentiation and that lactate serves both as a crucial TCA metabolite and promotes protein and histone lactylation and gene expression. These findings suggest that during skeletal growth, NP-derived lactate in part supports endplate cartilage differentiation into the vascularized subchondral bone, which, when absent, limits nutrient exchange and availability to the other disc compartments, affecting their homeostasis. This study provides the first in vivo evidence that loss of MCT1 mediated lactate uptake in endplate cells causes delayed maturation and intervertebral disc degeneration.
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