# The Branched Chain Ketoacid Dehydrogenase Kinase-Phosphatase System as a New Regulatory Node in Mycocardial Fuel Section

> **NIH NIH K08** · DUKE UNIVERSITY · 2021 · $142,606

## Abstract

Despite major treatment advances over the last decades, mortality after the onset of heart failure (HF)
symptoms remains extremely high. Changes in cardiac metabolic pathways, a process termed metabolic
remodeling, precedes the structural remodeling that occurs with HF progression. During HF, branched-chain
amino acids (BCAA) and branched-chain ketoacids (BCKA) increase in circulation. Moreover, the cardiac
BCAA metabolic pathway becomes impaired, leading to increased cardiac BCAA and BCKA. The impact of
systemic and cardiac-specific BCAA dysregulation on HF pathogenesis is still largely unknown. Using animal
models of HF, we have found that HF per se impairs hepatic BCAA metabolism, which may explain the
increase in circulating BCAA and BCKA. Additionally, we have found that, in contrast to previous reports, there
is negligible entry of cardiac BCAA into the TCA cycle (i.e. anaplerosis). Rather, the heart tends to salvage the
BCAA pool through conversion of BCKA into BCAA. Taken together, these findings suggest an unappreciated
metabolic interplay between the heart and liver that increases delivery of BCAA and BCKA to the failing heart.
Moreover, cardiac BCAA metabolism appears to affect the metabolism of other substrates such as glucose
and fatty acids. We recently discovered, in the liver, that the regulatory enzymes that control BCAA metabolism
in the mitochondria also regulate a cytosolic enzyme that coordinates glucose and lipid metabolism. It is
unknown whether this new metabolic regulatory node has a role in HF. The overall objective of this application
is to determine the role of dysregulated systemic and cardiac-specific BCAA metabolism in structural and
metabolic remodeling in HF. Our specific aims are (1) To determine how dysregulation of hepatic and cardiac
BCAA metabolism during HF contributes to HF pathogenesis and (2) To determine if the regulatory system of
cardiac BCAA metabolism also influences fuel preference in the failing heart. To achieve Aim 1, we will
generate liver- and heart-specific knockout mice that promote hepatic or cardiac BCAA catabolism,
respectively. We will then induce HF in these animals and will characterize the functional and molecular
changes in the heart to determine how organ-specific alterations in BCAA metabolism affect HF progression.
To achieve Aim 2, we will use state-of-the art metabolic flux techniques in isolated beating hearts from these
animals to determine how the genetic manipulations affect cardiac fuel use. If successful, these studies will
define new mechanistic bases for structural and metabolic remodeling in the failing heart.
Together, these experiments will allow me to build on the following skills: 1) basic biochemical, molecular and
metabolic research techniques; 2) generation and utilization of animal models of cardiac disease; and 3)
cardiac metabolic and physiological phenotyping. The data gathered during this award period coupled with
mentorship from leaders in the fields of basi...

## Key facts

- **NIH application ID:** 10140407
- **Project number:** 5K08HL135275-04
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Robert Walker McGarrah
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $142,606
- **Award type:** 5
- **Project period:** 2018-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10140407

## Citation

> US National Institutes of Health, RePORTER application 10140407, The Branched Chain Ketoacid Dehydrogenase Kinase-Phosphatase System as a New Regulatory Node in Mycocardial Fuel Section (5K08HL135275-04). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10140407. Licensed CC0.

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