# ACADSB-dependent skeletal muscle gene expression in relation to cardiorespiratory fitness

> **NIH NIH F31** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2022 · $33,764

## Abstract

ABSTRACT
Individuals with higher cardiorespiratory fitness (CRF) experience decreased rates of obesity and
cardiometabolic disease and show significantly lower age-adjusted and disease-adjusted mortality. Given the
increasing rates of obesity and cardiometabolic disease and the negative consequences of these diseases on
quality of life and the healthcare system, there is a need to understand the intrinsic molecular mechanisms that
contribute to the higher fitness phenotype. Although it is predicted that CRF is highly genetically heritable, it is
unknown how the inheritance of specific genes contributes to the health and longevity associated with CRF.
To study the genetic heritability of CRF, our lab has been characterizing a rat bred for high (HCR) and low
(LCR) CRF via generational selective breeding for fitness which originated from a genetically heterogeneous
stock. HCR rats phenocopy high-CRF traits in humans including leanness, longevity, and increased expression
of genes related to mitochondrial oxidative phosphorylation, fatty acid (FA) metabolism, and branch chain
amino acid (BCAA) metabolism in the skeletal muscle. Genetic and phenotypic heterogeneity is conserved
within the HCR and LCR lines through rotational breeding, such that the interaction between genes and
phenotype can be studied. One of the most highly and consistently upregulated genes in the skeletal muscle of
HCR rats is ACADSB, a BCAA and short-chain FA catabolic enzyme whose key end metabolic product is
propionate. Unpublished genotyping studies have identified statistically significant QTL and eQTL associations
of an allelic variant near ACADSB. We hypothesize that ACADSB regulates the expression of genes related to
oxidative metabolism and reduced disease risk in part by increased generation of propionate, an HDAC-
inhibitor, in skeletal muscle. Specifically, HCR rats more highly express a shorter splice variant of ACADSB,
raising the question of whether the HCR-associated isoform, or the total ACADSB concentration, potentially
leads to differential gene expression. My project will test this hypothesis by (1) overexpressing LCR and HCR-
associated splice variants of ACADSB in the skeletal muscle of both HCR and LCR rats, assessing the global
changes in skeletal muscle gene expression with RNA-Seq, and observing the changes in metabolic flux
through ACADSB, and (2) supplementing HCR and LCR rats with propionate to assess global transcriptional
regulation and changes in chromatin histone post-translational modifications.

## Key facts

- **NIH application ID:** 10453441
- **Project number:** 5F31DK130253-02
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Johanna Fleischman
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $33,764
- **Award type:** 5
- **Project period:** 2021-07-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10453441

## Citation

> US National Institutes of Health, RePORTER application 10453441, ACADSB-dependent skeletal muscle gene expression in relation to cardiorespiratory fitness (5F31DK130253-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10453441. Licensed CC0.

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