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

Award Number: K08HL147377
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 04/15/2019
PERIOD OF PERFORMANCE END DATE: 12/31/2024

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Fibro-adipogenic remodeling of the diaphragm in obesity-associated respiratory dysfunction - 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-Seq and human sample analysis.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2023	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE STE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	National Center on Sleep Disorders Research	000	5	3/6/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $169,560 )
2023	2023	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON STREET	ANN ARBOR	MI	48109	WASHTENAW	USA	National Center on Sleep Disorders Research	000	5	3/28/2023	NON-COMPETING CONTINUATION	$169,560
														Subtotal = $169,560

Issue Date FY: 2022 ( Subtotal = $169,560 )
2022	2022	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	National Center on Sleep Disorders Research	000	4	3/17/2022	NON-COMPETING CONTINUATION	$169,560
														Subtotal = $169,560

Issue Date FY: 2021 ( Subtotal = $169,560 )
2021	2021	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	National Center on Sleep Disorders Research	000	3	3/27/2021	NON-COMPETING CONTINUATION	$169,560
														Subtotal = $169,560

Issue Date FY: 2020 ( Subtotal = $169,560 )
2020	2020	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	National Center on Sleep Disorders Research	000	2	3/19/2020	NON-COMPETING CONTINUATION	$169,560
														Subtotal = $169,560

Issue Date FY: 2019 ( Subtotal = $169,464 )
2019	2019	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	National Center on Sleep Disorders Research	000	1	4/18/2019	NEW	$169,464
														Subtotal = $169,464

Grand Total All Awards = $847,704

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

Award Number: K08HL147377

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 04/15/2019

PERIOD OF PERFORMANCE END DATE: 12/31/2024

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