# Mitochondrially Targeted Therapies for Sepsis Induced Diaphragm Dysfunction

> **NIH NIH R01** · UNIVERSITY OF KENTUCKY · 2020 · $542,781

## Abstract

Severe ICU acquired diaphragm dysfunction is present in the majority of mechanically ventilated MICU
patients. Importantly, recent work indicates that patients with weak diaphragms have a much longer
requirement for mechanical ventilation and a markedly higher mortality. As a result, therapies that increase
diaphragm function have the potential to improve MICU patient outcomes. These recent studies also suggest
that a major risk factor for ICU acquired diaphragm weakness is infection. Infections elicit a marked increase
in diaphragm mitochondrial free radical production, and these free radicals contribute to weakness and
fatigue. The present proposal, therefore, will test the hypothesis that pharmacological therapies
designed to either inhibit mitochondrial free radical generation or induce mitochondrial repair will
prevent and/or reverse sepsis mediated diaphragm dysfunction. This theory will be tested in four
groups of studies:
Aim 1 studies will test the hypothesis that sepsis induced diaphragm dysfunction can be reduced by using
agents which inhibit mitochondrial free radicals. Experiments will utilize the cecal ligation puncture sepsis
model (CLP) and compare diaphragm function in sham operated, CLP, CLP plus drug, and sham plus drug
groups. Drugs to be tested include mitoTEMPOL, SKQ1, and necrostatin.
Aim 2 studies will test the hypothesis that administration of activators of mitochondrial biogenesis can
improve infection induced diaphragm dysfunction. Sepsis will again be produced with CLP and we will
examine the ability of three treatments (i.e. AICAR+PQQ, PQQ, and AICAR+GW1506) to prevent CLP
induced diaphragm dysfunction.
Aim 3 studies will evaluate the mechanisms by which Aim 1 and Aim 2 drugs produce their effects on
muscle cells. These experiments will also test the hypothesis that these agents induce release of myokines
which have autocrine effects to attenuate cytokine induced muscle cell damage.
Aim 4 studies will test the hypothesis that myokine administration can be used as a pharmacological
treatment to attenuate sepsis induced diaphragm dysfunction in animals. Myokines to be tested include irisin
and other proteins found in Aim 3 studies to block cytokine induced muscle cell damage in vitro.

## Key facts

- **NIH application ID:** 9952417
- **Project number:** 5R01HL141356-03
- **Recipient organization:** UNIVERSITY OF KENTUCKY
- **Principal Investigator:** LEIGH A CALLAHAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $542,781
- **Award type:** 5
- **Project period:** 2018-07-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9952417

## Citation

> US National Institutes of Health, RePORTER application 9952417, Mitochondrially Targeted Therapies for Sepsis Induced Diaphragm Dysfunction (5R01HL141356-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9952417. Licensed CC0.

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