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

> **NIH NIH R01** · STANFORD UNIVERSITY · 2021 · $597,186

## Abstract

ABSTRACT
COVID-19 symptom severity is directly linked to age as well as other comorbidities such as diabetes, poor
respiratory function, and cardiovascular disease. As of September 22, approximately 7.0 million cases of COVID-
19 have been reported in the US, and the overall cumulative COVID-19 hospitalization rate is high, with
individuals over age 65 twelve times as likely as those under 40 to be hospitalized for COVID-19. While in the
hospital, many COVID-19 patients require respiratory support from a ventilator. Although many patients survive
COVID-19, recovery is prolonged due to diaphragm muscle weakness and some never completely recover due
to ventilator-induced diaphragm dysfunction (VIDD), a condition that reduces the ability of a patient to be weaned
to independent breathing. VIDD risk and severity increase in elderly COVID-19 patients who are particularly
susceptible because they spend weeks, as opposed to days, immobilized and on mechanical ventilation.
There is currently no treatment for VIDD. This project proposes to acquire preclinical data in support of a therapy
for VIDD that utilizes a promising new small molecule that acts by a mechanism different from previously tested
therapeutics developed to treat VIDD. Our preliminary data suggest that Prostaglandin E2 (PGE2), the target of
our drug, acts on both muscle stem cells (MuSCs) to augment their proliferation and regenerative function, and
on mature myofibers to improve strength, particularly in the elderly. We hypothesize that PGE2/EP4 signaling
will act in aged diaphragm muscles as in aged limb muscles and can be modulated to improve diaphragm muscle
function. Specifically, we aim to (i) demonstrate that PGE2 augments the proliferative and regenerative function
of MuSCs isolated from human diaphragm biopsies obtained 4 hr after patients are put on a ventilator and (ii)
assess the efficacy of our drug in enhancing MuSC function and promoting myofiber hypertrophy to counter
diaphragm atrophy in a rodent model of VIDD. Toward these goals, we will utilize human diaphragm biopsies
obtained from young (< 40yr) and elderly (> 65yr) patients at the time of cardiothoracic surgery and perform both
functional assays of PGE2 treated human MuSC regenerative capacity in culture and following transplantation
into immunodeficient mice. We will also assess in human diaphragm if the rapid atrophy induced by a ventilator
leads to a decline in PGE2 levels and disruption of TGF-beta, cAMP/CREB, and AKT/FOXO signaling pathways.
Finally, we will determine if PGE2 elevation via our therapeutic improves diaphragm function and regenerative
capacity in the context of mechanical ventilation in a well-established rodent model of VIDD, which causes
diaphragm atrophy and reduced contractile force. The project is a preclinical collaboration between Stanford
faculty, Dr. Helen Blau, who characterized a novel small molecule drug as a potential therapeutic for sarcopenia,
and Dr. Joseph Shrager, a prominent card...

## Key facts

- **NIH application ID:** 10272407
- **Project number:** 3R01AG069858-02S1
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Helen M Blau
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $597,186
- **Award type:** 3
- **Project period:** 2020-09-15 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10272407

## Citation

> US National Institutes of Health, RePORTER application 10272407, Regulation of eicosanoid signaling lipids to improve skeletal muscle function and increase healthspan during aging (3R01AG069858-02S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10272407. Licensed CC0.

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