{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T12:42:18Z","timestamp":1793104938095,"version":"4.5.0"},"reference-count":93,"publisher":"American Society for Clinical Investigation","issue":"16","license":[{"start":{"date-parts":[[2024,8,22]],"date-time":"2024-08-22T00:00:00Z","timestamp":1724284800000},"content-version":"vor","delay-in-days":51,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000052","name":"NIH Office of the Director","doi-asserted-by":"crossref","award":["HL14737701,DK095137,AR069620,DK135066,DK020572,DK089503"],"award-info":[{"award-number":["HL14737701,DK095137,AR069620,DK135066,DK020572,DK089503"]}],"id":[{"id":"10.13039\/100000052","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,8,22]]},"abstract":"<jats:p>\n                    Pulmonary disorders affect 40%\u201380% 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) \u2014 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\n                    <jats:italic>Thbs1<\/jats:italic>\n                    -knockout (\n                    <jats:italic>\n                      Thbs1\n                      <jats:sup>\u2013\/\u2013<\/jats:sup>\n                    <\/jats:italic>\n                    ) mice. Bulk and single-cell transcriptomics demonstrated DIO-induced stromal expansion in WT diaphragms. Diaphragm FAPs displayed upregulation of ECM and TGF-\u03b2\u2013related expression signatures and augmentation of a\n                    <jats:italic>Thy1<\/jats:italic>\n                    -expressing subpopulation previously linked to type 2 diabetes. Despite similar weight gain,\n                    <jats:italic>\n                      Thbs1\n                      <jats:sup>\u2013\/\u2013<\/jats:sup>\n                    <\/jats:italic>\n                    mice were protected from these transcriptomic changes and from obesity-induced increases in diaphragm adiposity and ECM deposition. Unlike WT controls,\n                    <jats:italic>\n                      Thbs1\n                      <jats:sup>\u2013\/\u2013<\/jats:sup>\n                    <\/jats:italic>\n                    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.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.175047","type":"journal-article","created":{"date-parts":[[2024,7,2]],"date-time":"2024-07-02T12:01:53Z","timestamp":1719921713000},"source":"Crossref","is-referenced-by-count":5,"title":["Thrombospondin-1 promotes fibro-adipogenic stromal expansion and contractile dysfunction of the diaphragm in obesity"],"prefix":"10.1172","volume":"9","author":[{"given":"Eric D.","family":"Buras","sequence":"first","affiliation":[{"name":"Division of Metabolism, Endocrinology and Diabetes (MEND), Department of Internal 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