# Mechanism by which fatty acid metabolism impacts muscle maintenance

> **NIH NIH R01** · UNIVERSITY OF COLORADO · 2023 · $338,800

## Abstract

Project Summary
 Due to their essential roles in fundamental biological processes (e.g., energy production and
membrane formation), the availability of fatty acids (FAs) profoundly impacts the initiation and
progression of various cellular and developmental events in animals. In particular, fat or FA levels have
long been proposed to promote reproductive development, as well as neuronal and muscle functions for
foraging ability under fasting conditions. Extensive studies have also revealed a cause/effect relationship
between abnormal FA metabolism and pathologic conditions, including age-related neurological and
muscular diseases. However, mechanisms underlying the impact of FA levels on specific physiological
functions, especially functions regulated by FA-sensing mechanisms in specific tissues, have been
underexplored. Our recent study found that an acyl-coA synthetase and protein myristoylation act as a
FA sensor in the germline to regulate the onset of oogenesis by modulating the sex-determination.
Based on this finding, we propose to elucidate the mechanisms by which FA availability regulates muscle
maintenance and provide insights into the pathogenesis of FA metabolism-related degenerative
diseases. We have obtained extensive preliminary data for a hypothesis where myristoylation deficiency
of two ARF GTPases, and other proteins in muscle, mediate the impact of FA deficiency on sarcomere
integrity by inducing ER stress and unfolded protein responses (UPR) that are known to be involved in
the genesis of major diseases. We proposed three specific research aims to further investigate this
hypothesis and the underlying mechanism. In Aim 1, we will use both molecular and genetic approaches
to determine the role of myristoylation in muscle to maintain sarcomere integrity. Myristoylation level and
subcellular localization of specific regulatory factors will be examined for roles in mediating the effect of
FA level change on muscle functions. In Aim 2, we will analyze the role of ER stress and UPR in
mediating the impact of myristoylation deficiency on muscle maintenance. We will first characterize ER
stress and changes in the 3 UPR pathways in responding to FA and myristoylation deficiency. We will
then test if experimentally inducing ER stress causes muscle defects similar to that from myristoylation
deficiency, and whether repressing ER stress can rescue the muscle functions under myristoylation
deficiency. For Aim 3, we will turn our attention to understanding how myristoylation and ER stress
impact muscle integrity. We will use two systematic approaches, one expression analysis-initiated and
one based on a suppressor screen, to search for factors that act downstream of or in parallel to UPRER in
FA/myristoylation deficiency-induced muscle defects. We have already started analyzing one promising
candidate, UNC-97/PINCH, that appears to play a significant role in the process. The proposed research
will make significant advances in our understand...

## Key facts

- **NIH application ID:** 10656381
- **Project number:** 5R01AR074503-05
- **Recipient organization:** UNIVERSITY OF COLORADO
- **Principal Investigator:** MIN HAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $338,800
- **Award type:** 5
- **Project period:** 2019-07-15 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10656381

## Citation

> US National Institutes of Health, RePORTER application 10656381, Mechanism by which fatty acid metabolism impacts muscle maintenance (5R01AR074503-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10656381. Licensed CC0.

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