# Pyruvate and acetate metabolism after TBI: implications for cerebral energy metabolism

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2022 · $556,083

## Abstract

A major challenge of treating traumatic brain injury (TBI) patients is the simultaneously occurring complex
secondary injury processes following the primary injury. The secondary events such as cerebral
hyperglycolysis and mitochondrial failure develop over minutes to months after the primary injury, providing a
potential window of opportunity for therapeutic intervention. Given early, this intervention may prevent or
reduce secondary brain damage, directly impacting long-term patient outcome. Therefore, the noninvasive
detection and characterization of pathophysiology in TBI patients during the acute and early sub-acute stages,
will have critical clinical implications for the early diagnosis of individuals with the highest risk of poor
neurological outcomes and will be vital for identifying and developing effective therapies. While a number of
pathological alternations in TBI are potential biomarkers, no current clinical imaging modalities are sensitive
enough to be routinely used to detect the details of metabolic shifts in brain sub-regions with secondary injury.
Magnetic resonance spectroscopic imaging (MRSI) of hyperpolarized 13C-labeled substrates provides unique
noninvasive measurements of critical in vivo dynamic metabolic processes. In particular, pyruvate occupies a
key nodal point in cerebral energy metabolism, among the fates of [1-13C]pyruvate are reduction to lactate as
the end product of glycolysis, conversion in mitochondria to form acetyl-CoA and CO2 (detected as HCO3–) via
pyruvate dehydrogenase (PDH) flux or anaplerotic pyruvate carboxylase (PC) pathway for oxidative
phosphorylation. [2-13C]pyruvate, on the other hand, directly assess the tricarboxylic acid (TCA) cycle by
detecting [5-13C]glutamate production. While our preliminary data demonstrated increased lactate and
decreased HCO3– (bicarbonate) production from hyperpolarized [1-13C]pyruvate in a rat TBI model and acute
TBI patients, however, the role of [13C]HCO3– as a TCA cycle marker needs further verification due to the high
pyruvate carboxylation. Another key metabolic alteration following TBI is increased acetate oxidation in
astrocytes, playing a neuro-protective role. The increased acetate metabolism tightly interacts with pyruvate
metabolism, and thus, should be considered together when interpreting [13C]pyruvate metabolism.
The fundamental goal of this project is to understand how TBI influences the in vivo cellular metabolism in the
brain using hyperpolarized 13C MRSI as a step towards personalizing therapy for TBI patients. In this proposal,
a comprehensive analysis of TBI metabolism will be performed using a rat TBI model by comparing the in vivo
imaging results with ex vivo tissue analysis. First, we will develop hyperpolarized [2-13C]pyruvate as a probe to
directly measure the altered TCA cycle activity in TBI (aim 1). Second, we will assess the contribution of
increased acetate metabolism to pyruvate oxidation in a rat TBI model (aim 2). The longitudinal in...

## Key facts

- **NIH application ID:** 10487464
- **Project number:** 5R01NS107409-03
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Jae Mo Park
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $556,083
- **Award type:** 5
- **Project period:** 2020-09-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10487464

## Citation

> US National Institutes of Health, RePORTER application 10487464, Pyruvate and acetate metabolism after TBI: implications for cerebral energy metabolism (5R01NS107409-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10487464. Licensed CC0.

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