# A novel role for oxidized lipid mediators as effectors of muscle atrophy and weakness in aging

> **NIH NIH R01** · OKLAHOMA MEDICAL RESEARCH FOUNDATION · 2024 · $546,925

## Abstract

Abstract. Sarcopenia, the loss of muscle mass and function with age, is a universal problem in the growing
elderly population. To design effective interventions we need to better understand the mechanism(s) responsible
for initiation and progression of muscle atrophy and weakness in aging. Studies from our lab and others have
shown that loss of innervation is a key driver of muscle atrophy with age. The goal of this proposal is to test
a novel hypothesis that bioactive lipid mediators (oxylipins and oxidized phospholipids (oxPL)), are
primary effectors for muscle atrophy and weakness. Our hypothesis is strongly supported by our data
showing that denervation induces activation of phospholipase A2 (cPLA2), releasing arachidonic acid (AA) from
muscle membranes that can promote generation of oxidized lipids, either non-enzymatically or via 12/15
lipoxygenase (Alox15) dependent generation. We have also shown that denervation-induced muscle loss is
decreased when AA release and oxidized lipids are blocked by inhibition of cPLA2 or Alox15, or by scavenging
of LOOH using liproxstatin-1 or Gpx4Tg mice, thus supporting oxPL/oxylipins as a critical mechanistic link
between denervation and muscle wasting. However, the mechanisms by which oxPL/oxylipins cause muscle
atrophy have not been defined. Based on previously identified targets of these lipid mediators, we are specifically
testing the hypothesis that oxPL/oxylipins induced by denervation cause damage to membranes,
promote mitochondrial changes and activate proteolytic and cell death pathways to induce age-related
muscle atrophy. In Aim 1, we will define the effect of modulating oxylipins on atrophy related targets by inhibiting
generation of oxPL/oxylipins (using cPLA2KO and Alox15KO mice) and by altering reduction of lipid
hydroperoxides (using Gpx4/Tg and muscle specific Gpx4KO mice and treatment with liproxstatin-1) on
membrane oxidative damage, mitochondrial function, muscle degradative and cell death pathways and muscle
mass after denervation. These experiments will identify the primary oxylipins produced in denervated muscle
and identify the critical targets of oxylipins that lead to muscle atrophy and weakness. In Aim 2, we will measure
the effect of key oxylipins identified in Aim 1 in vitro in C2C12 muscle cells on oxidative damage, mitochondrial
function, protein degradation pathways and muscle fiber diameter. These experiments will provide new
information on the effect of specific oxylipins on muscle metabolism and mitochondrial function. Finally, in Aim
3, we will test whether inhibiting oxylipin generation in vivo in muscle specific Alox15KO mice or reducing levels
of lipid hydroperoxides (LOOH) in mice with elevated levels of Gpx4 expression can protect against age-related
muscle atrophy in vivo in aging mice. We predict that reduced generation of oxPL/oxylipins and enhanced
detoxification of lipid hydroperoxides (LOOH) will modify the atrophy targets outlined in Aim 1, reducing muscle
at...

## Key facts

- **NIH application ID:** 10864995
- **Project number:** 5R01AG077812-03
- **Recipient organization:** OKLAHOMA MEDICAL RESEARCH FOUNDATION
- **Principal Investigator:** HOLLY VAN REMMEN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $546,925
- **Award type:** 5
- **Project period:** 2022-09-30 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10864995

## Citation

> US National Institutes of Health, RePORTER application 10864995, A novel role for oxidized lipid mediators as effectors of muscle atrophy and weakness in aging (5R01AG077812-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10864995. Licensed CC0.

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