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Publication
Thrombospondin-1 promotes fibro-adipogenic stromal expansion and contractile
dysfunction of the diaphragm in obesity.
Authors Buras ED, Woo MS, Kaul Verma R, Kondisetti SH, Davis CS, Claflin DR,
Converso-Baran K, Michele DE, Brooks SV, Chun TH
Submitted By Submitted Externally on 10/15/2024
Status Published
Journal JCI insight
Year 2024
Date Published 7/1/2024
Volume : Pages 9 : Not Specified
PubMed Reference 38954467
Abstract Pulmonary disorders affect 40%-80% of individuals with obesity. Respiratory
muscle dysfunction is linked to these conditions; however, its pathophysiology
remains largely undefined. Mice subjected to diet-induced obesity (DIO) develop
diaphragm muscle weakness. Increased intradiaphragmatic adiposity and
extracellular matrix (ECM) content correlate with reductions in contractile
force. Thrombospondin-1 (THBS1) is an obesity-associated matricellular protein
linked with muscular damage in genetic myopathies. THBS1 induces proliferation
of fibro-adipogenic progenitors (FAPs) - mesenchymal cells that differentiate
into adipocytes and fibroblasts. We hypothesized that THBS1 drives FAP-mediated
diaphragm remodeling and contractile dysfunction in DIO. We tested this by
comparing the effects of dietary challenge on diaphragms of wild-type (WT) and
Thbs1-knockout (Thbs1-/-) mice. Bulk and single-cell transcriptomics
demonstrated DIO-induced stromal expansion in WT diaphragms. Diaphragm FAPs
displayed upregulation of ECM and TGF-ß-related expression signatures and
augmentation of a Thy1-expressing subpopulation previously linked to type 2
diabetes. Despite similar weight gain, Thbs1-/- mice were protected from these
transcriptomic changes and from obesity-induced increases in diaphragm adiposity
and ECM deposition. Unlike WT controls, Thbs1-/- diaphragms maintained normal
contractile force and motion after DIO challenge. THBS1 is therefore a necessary
mediator of diaphragm stromal remodeling and contractile dysfunction in
overnutrition and a potential therapeutic target in obesity-associated
respiratory dysfunction.




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