# Fibro-adipogenic remodeling of the diaphragm in obesity-associated respiratory dysfunction

> **NIH NIH K08** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2022 · $169,560

## Abstract

Abstract:
Obesity-associated respiratory complications range from simple dyspnea on exertion to life-threatening obesity
hypoventilation syndrome (OHS). The latter, defined by PaCO2 >45 torr in individuals with body mass index
(BMI) >30kg/m2 and no alternative cause of hypercapnia, is associated with severe cardiac complications and
increased mortality. While inability of the lungs to expand against abdominal and thoracic adipose tissue is
thought to drive this ventilatory compromise, clinical studies have also identified respiratory muscle weakness in
obese patients. Moreover, large adipocyte inclusions are seen in diaphragms of subjects with OHS but not in
obese/normocapnic or lean individuals. These findings suggest the diaphragm itself may be compromised with
obesity; however, impacts of over-nutrition on structure and function of this muscle are not well defined. In mice
subjected to a long-term diet-induced obesity (DIO) time course, we observed hypercapnia after 6 months high
fat diet (HFD) feeding. This temporally corresponded with impaired diaphragm muscle function—assessed in
vivo by ultrasonography and ex vivo by measurement of contractile force. Adipose tissue expansion and collagen
deposition within the diaphragm temporally corresponded with hypercapnia and quantitatively correlated with ex
vivo contractile deficits. Lineage tracing showed all intra-diaphragmatic adipocytes and many collagen-producing
cells to arise from fibro-adipogenic progenitors (FAPs), a skeletal muscle mesenchymal stem cell population.
FAP number, proliferation, and collagen deposition increased with obesity.
We hypothesize that FAP-mediated, fibro-adipogenic remodeling of the diaphragm impairs ventilatory
function in obesity. In Aim 1, we will test whether obesity per se impairs ventilation and diaphragm function by
analyzing weight-matched genetically obese and DIO mice. Ex vivo, we will measure contractile function and
passive stiffness of large muscle isolates and individual myofibers to determine whether biomechanical defects
occur at the tissue or cellular level. Finally, we will determine quantitative correlations of intra-diaphragmatic
adipocyte number and polymerized collagen with these physiologic parameters. In Aim 2, we specifically test
the hypothesis that FAPs mediate diaphragm fibro-adipogenic remodeling and dysfunction in obesity. We will
analyze FAP response to obesity with global gene expression profiling and ex vivo proliferation, adipogenesis
and collagen deposition quantification. We will then determine whether (diphtheria toxin-mediated) FAP ablation
prevents diaphragm fibro-adipogenic changes and dysfunction in a DIO model. In Aim 3, we will analyze tissue
samples and FAPs isolated from human autopsy samples to determine whether similar changes occur in obese
humans and associate with clinical OHS diagnosis. The work will define a cellular mechanism of OHS; and
completion of the project will provide training in muscle biomechanics, RNA-Se...

## Key facts

- **NIH application ID:** 10379062
- **Project number:** 5K08HL147377-04
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** ERIC D BURAS
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $169,560
- **Award type:** 5
- **Project period:** 2019-04-15 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10379062

## Citation

> US National Institutes of Health, RePORTER application 10379062, Fibro-adipogenic remodeling of the diaphragm in obesity-associated respiratory dysfunction (5K08HL147377-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10379062. Licensed CC0.

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