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

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2024 · $406,505

## Abstract

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.

## Key facts

- **NIH application ID:** 10898901
- **Project number:** 5R01AR081234-03
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Gwendolyn A Sowa
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $406,505
- **Award type:** 5
- **Project period:** 2022-09-15 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10898901

## Citation

> US National Institutes of Health, RePORTER application 10898901, Metabolic Symbiosis: Lactate as an Epigenetic Regulator and a Biofuel in Age-dependent Intervertebral Disc Degeneration (5R01AR081234-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10898901. Licensed CC0.

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