# The effect of intermittent hemidiaphragm stimulation during surgery on mitochondrial function, single fiber contractile force and catabolic pathways in humans

> **NIH NIH R01** · UNIVERSITY OF FLORIDA · 2020 · $408,978

## Abstract

Although mechanical ventilation (MV) is life-sustaining in patients with respiratory failure, it comes with a cost.
MV dramatically reduces diaphragm contractility, induces ventilator-induced diaphragm dysfunction (VIDD) and
sometimes leads to weaning failure. VIDD includes reduced mitochondrial respiration and increased oxidative
stress, muscle fiber damage and decreased diaphragm force production. In animal models, intermittent
diaphragm contraction during MV support attenuates VIDD. However, there are only limited data addressing
this problem in humans. Here, we propose to directly test the hypothesis that intermittent electrical stimulation
(ES) of the human hemidiaphragm during prolonged cardiac surgeries with MV support prevents/attenuates
VIDD in the active hemidiaphragm.
Mitochondrial function is central to energy metabolism and skeletal muscle function in a chronically active
muscle, such as the diaphragm. Although abnormal mitochondrial function is thought to precipitate VIDD in
animal models, limited data are available concerning mitochondrial contributions to VIDD in humans. Of even
greater importance, there are no interventions available to attenuate these defects in humans. Here, we will
test the impact of an innovative experimental treatment, intermittent electrical stimulation (ES) of the
hemidiaphragm during prolonged surgeries with MV, on mitochondrial function, single fiber contractile
properties and catabolic muscle pathways in human diaphragm. Using a within-subjects experimental design,
muscle samples from a stimulated hemidiaphragms will be compared with samples from the unstimulated
hemidiaphragm. We will investigate mitochondrial dysfunction and oxidative stress during prolonged CTS/MV,
and the potential of ES to attenuate or prevent VIDD (Aim 1). Next, we will investigate the effects of ES on
single fiber contractile properties and Titin integrity (Aim 2). Finally, we will study the effect of ES on proteolytic
pathways (caspase, calpain and ubiquitin-proteasome) and ribosomal RNA markers of decreased protein
synthesis implicated in VIDD (Aim 3).
This research will provide evidence concerning the ability to improve mitochondrial function in the stimulated
hemidiaphragm, and identify mechanisms contributing to human VIDD. Our long-term goal is to test various
intermittent hemidiaphragm ES protocols on a larger population to determine its ability to prevent or attenuate
VIDD. Data from this R01 application will advance our understanding of mechanisms giving rise to human
VIDD, and may inspire new therapeutic strategies to maintain human diaphragm function during MV support.

## Key facts

- **NIH application ID:** 9932892
- **Project number:** 5R01AR072328-04
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** THOMAS M BEAVER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $408,978
- **Award type:** 5
- **Project period:** 2017-07-27 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9932892

## Citation

> US National Institutes of Health, RePORTER application 9932892, The effect of intermittent hemidiaphragm stimulation during surgery on mitochondrial function, single fiber contractile force and catabolic pathways in humans (5R01AR072328-04). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/9932892. Licensed CC0.

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