# Regulation of substrate metabolism in skeletal muscle by mitochondrial thioesterases

> **NIH NIH R01** · THOMAS JEFFERSON UNIVERSITY · 2020 · $390,000

## Abstract

Abstract
Disturbed glucose homeostasis, particularly in skeletal muscle, is a fundamental contributor to type 2 diabetes.
Despite the known importance of lipid metabolism in regulating glucose metabolism, the role of mitochondria in
this regulation has been contentious. The objective here is to define the role of acyl-CoA thioesterase-2 (Acot2)
in skeletal muscle lipid and glucose metabolism. Acot2 resides within the mitochondrial matrix and hydrolyzes
long-chain fatty-acyl CoA. Its biological role is unknown. We hypothesize that Acot2 provides a safety valve to
limit the flow of long-chain fatty acyl-CoA into β-oxidation, thereby curbing the abundance of long-chain fatty
acyl-CoA and acetyl-CoA in the mitochondrial matrix. Acetyl-CoA accumulation within muscle mitochondria has
been linked to disturbed systemic glucose homeostasis and to a lesser ability to switch between glucose and
lipid oxidation (metabolic flexibility) in muscle. Thus, we also hypothesize that Acot2 in muscle promotes
substrate switching and contributes to glucose homeostasis. We base these hypotheses on Preliminary
Studies from our lab showing that Acot2 dampens β-oxidation and lipid-induced reactive oxygen species
production, enables better matching between β-oxidation and oxidative phosphorylation, and improves
metabolic flexibility at the level of mitochondria and glucose homeostasis systemically. We have also observed
that Acot2 is required for the full activity of carnitine acetyltransferase (CrAT) which was recently shown to be
required for normal substrate switching in muscle and systemic glucose homeostasis. The rationale here is that
identifying the biological role of Acot2 will provide new insight into the mechanisms by which mitochondria
regulate skeletal muscle glucose disposal, and thus systemic glucose homeostasis. The hypothesis will be
tested in three specific aims to define how Acot2: 1) influences substrate metabolism and uncoupled
respiration in skeletal muscle mitochondria; 2) impacts glucose disposal and substrate switching in skeletal
muscle and whether Acot9 compensates for Acot2 absence; 3) determines redox state of the mitochondrial
matrix, and if perturbed mitochondrial redox influences glucose homeostasis when Acot2 is absent. Studies will
utilize a new Acot2 loss-of-function model and CrAT gain-of-function, and will integrate observations from
bioenergetics, radioisotope, metabolomics analyses and imaging experiments, on different muscle
preparations, with tissue and whole-body metabolism. These studies are innovative because they approach
skeletal muscle metabolism from an understudied pathway of mitochondrial long-chain fatty-acyl hydrolysis.
The significance of studying this pathway is indicated by our findings that this pathway can broadly influence
systemic glucose homeostasis.

## Key facts

- **NIH application ID:** 9951036
- **Project number:** 5R01DK109100-04
- **Recipient organization:** THOMAS JEFFERSON UNIVERSITY
- **Principal Investigator:** Erin Seifert
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $390,000
- **Award type:** 5
- **Project period:** 2017-07-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9951036

## Citation

> US National Institutes of Health, RePORTER application 9951036, Regulation of substrate metabolism in skeletal muscle by mitochondrial thioesterases (5R01DK109100-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9951036. Licensed CC0.

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