# Regulation of eicosanoid signaling lipids to improve skeletal muscle function and increase healthspan during aging

> **NIH NIH R01** · STANFORD UNIVERSITY · 2020 · $401,555

## Abstract

PROJECT SUMMARY
Age-related muscle atrophy, or sarcopenia, affects 15% of the elderly, diminishing quality of life and increasing
morbidity and mortality. During aging, skeletal muscles undergo structural and functional alterations as a result
of multiple dysregulated pathways. Due to this multifactorial etiology, untangling the causal molecular pathways
in order to identify therapeutic targets to prevent, delay or reverse sarcopenia has proven challenging. Our goal
is to elucidate novel causal mechanisms of sarcopenia and use this knowledge to improve aged muscle function.
Our preliminary data has revealed a reduction in specific lipid prostaglandin metabolites in aged muscles. We
recently discovered that this reduction resulted from catabolism by 15-hydroxyprostaglandin dehydrogenase (15-
PGDH), the prostaglandin degrading enzyme, which is markedly increased in aged mouse and human muscles.
To determine the role of 15-PGDH in sarcopenia, we overexpressed the enzyme in young muscles, observed a
predicted reduction in PGE2 and PGD2 levels, which was accompanied by an unexpectedly marked decrease
in muscle mass and function, mimicking key features of sarcopenia. The discovery of 15-PGDH upregulation
and concomitant decrease in prostaglandin levels in aged muscle forms the basis for the proposed research and
enables targeted molecular and functional studies previously not possible. We hypothesize that during aging,
senescent and inflammatory cells accumulate in the muscle microenvironment and express 15-PGDH, which
degrades PGE2 and PGD2, and causes muscle wasting. We further hypothesize that inhibition of 15-PGDH in
aged muscles will increase PGE2 and PGD2 lipid metabolites and augment muscle mass and strength. In the
proposed research we aim to (i) elucidate the role of the lipid prostaglandin PGE2 and PGD2 metabolites in
skeletal muscle homeostasis, (ii) identify the cell source of 15-PGDH and prostaglandin dysregulation in aged
muscle, and (iii) restore muscle function and mass of aged muscles by inhibiting the catabolic enzyme, 15-
PGDH. This work will benefit from techniques we have previously developed to quantify prostaglandin levels:
mass-spectrometric-based lipid profiling and muscle force assessments over time using non-invasive methods.
Further, we will capitalize on a single-cell technology we recently optimized for the study of skeletal muscle
tissue, multiplexed tissue imaging (also known as CODEX, CO-Detection by indEXing), that resolves up to 60
markers simultaneously in single tissue sections. CODEX will enable a determination of whether senescent cells
comprise a cell source of 15-PGDH and resolution of spatial relationships among the diverse cell types in aged
muscles. Together, these studies will provide insights into a novel dysregulated pathway, lipid prostaglandin
signaling in aged muscles, and determine if inhibiting PGE2 and PGD2 catabolism mediated by 15-PGDH, aug-
ments aged muscle mass and function. This research will i...

## Key facts

- **NIH application ID:** 10095406
- **Project number:** 1R01AG069858-01
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Helen M Blau
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $401,555
- **Award type:** 1
- **Project period:** 2020-09-15 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10095406

## Citation

> US National Institutes of Health, RePORTER application 10095406, Regulation of eicosanoid signaling lipids to improve skeletal muscle function and increase healthspan during aging (1R01AG069858-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10095406. Licensed CC0.

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