Metabolic Symbiosis: Lactate as an Epigenetic Regulator and a Biofuel in Age-dependent Intervertebral Disc Degeneration

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Project Summary Intervertebral disc degeneration (IDD) underlies many spinal disorders and results in debilitating back pain, disability, and tremendous socioeconomic burden. The intervertebral disc (IVD) is the largest avascular organ comprised of a hypoxic nucleus pulposus (NP) center surrounded by an outer, more oxygenated annulus fibrosus (AF). The IVD contains copious amounts of lactic acid, which has long been viewed as a harmful waste byproduct of anaerobic glycolysis in the NP. However, we recently made two major advances that challenge this longstanding dogma. We demonstrated that AF cells can take up and utilize lactate as a carbon source via oxidative phosphorylation (OXPHOS), thus unveiling lactate-dependent metabolic symbiosis between NP and AF whereby the hypoxic NP cells make lactate to be used by the more aerobic AF cells as a carbon biofuel via OXPHOS. We also discovered high levels of IVD histone lactylation, a newly characterized type of histone post-translational modification (PTM) that uses lactate as a substrate precursor. Histone PTMs are critical to the dynamic modulation of chromatin structure and gene expression, and dysregulation of histone PTMs is closely linked with the development of many diseases. Based on our preliminary data, we hypothesize that disc lactate is not as a waste byproduct but rather serves as an important biofuel for the nutrient-poor disc and as a vital metabolic regulator of disc gene expression programming via histone lactylation. We propose three specific aims to test this hypothesis: (1) Determine whether lactate functions as an important metabolic regulator of disc gene expression through histone lactylation using rat disc cell culture models treated with chemical inhibitors of enzymes responsible for histone lactylation; (2) Determine whether disc histone lactylation and lactate- dependent metabolic symbiosis malfunction with age contributing to age-related IDD using young and old Fischer 344 rats; and (3) Determine whether interrupted disc lactate-dependent metabolic symbiosis disrupts disc histone lactylation pattern and promotes IDD using transgenic mouse models with AF-targeted genetic depletion to disrupt AF lactate uptake. Completion of the proposed studies will establish whether histone lactylation exerts epigenetic transcription regulation that controls disc matrix homeostasis and lactate-dependent metabolic symbiosis. Demonstrating the influences of lactate metabolism on age-related IDD through the mechanisms of epigenetic gene regulation and lactate-dependent metabolic symbiosis will be both novel and significant to identify new therapeutic targets to treat IDD with greater likelihood of success in the nutrient poor environment. This will be an innovative approach and significant advance over prior regenerative efforts which have had limited success in this unique tissue.