{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T20:02:28Z","timestamp":1768507348344,"version":"3.49.0"},"posted":{"date-parts":[[2023,8,19]]},"group-title":"Cell Biology","reference-count":87,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2023,8,19]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  Pulmonary disorders impact 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 diaphragmatic weakness. Increased intra-diaphragmatic 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)\u2014mesenchymal 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 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>-\/-<\/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-related expression signatures, and augmentation of a\n                  <jats:italic>Thy1<\/jats:italic>\n                  -expressing sub-population previously linked to type 2 diabetes. Despite similar weight gain,\n                  <jats:italic>\n                    Thbs1\n                    <jats:sup>-\/-<\/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>-\/-<\/jats:sup>\n                  <\/jats:italic>\n                  diaphragms maintained normal contractile force and motion after DIO challenge. These findings establish THBS1 as a necessary mediator of diaphragm stromal remodeling and contractile dysfunction in overnutrition, and potential therapeutic target in obesity-associated respiratory dysfunction.\n                <\/jats:p>","DOI":"10.1101\/2023.08.17.553733","type":"posted-content","created":{"date-parts":[[2023,8,19]],"date-time":"2023-08-19T16:00:12Z","timestamp":1692460812000},"source":"Crossref","is-referenced-by-count":0,"title":["Thrombospondin-1 promotes fibro-adipogenic stromal expansion and contractile dysfunction of the diaphragm in obesity"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7679-2484","authenticated-orcid":false,"given":"Eric D.","family":"Buras","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Moon-Sook","family":"Woo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Romil Kaul","family":"Verma","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sri Harshita","family":"Kondisetti","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carol S.","family":"Davis","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8044-0142","authenticated-orcid":false,"given":"Dennis R.","family":"Claflin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kimber Converso","family":"Baran","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel E.","family":"Michele","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1954-967X","authenticated-orcid":false,"given":"Susan V.","family":"Brooks","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9333-2589","authenticated-orcid":false,"given":"Tae-Hwa","family":"Chun","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2023082304250455000_2023.08.17.553733v1.1","first-page":"1-8","article-title":"Prevalence of Obesity and Severe Obesity Among Adults: United States, 2017-2018","volume":"360","year":"2020","journal-title":"NCHS Data Brief"},{"issue":"Suppl 1","key":"2023082304250455000_2023.08.17.553733v1.2","first-page":"S41\u20134","article-title":"Obesity, respiratory function and breathlessness","volume":"55","year":"2000","journal-title":"Thorax"},{"key":"2023082304250455000_2023.08.17.553733v1.3","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.200706-875OC"},{"key":"2023082304250455000_2023.08.17.553733v1.4","doi-asserted-by":"crossref","unstructured":"Whipp, B.J. and J.A. 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