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We hypothesized that cachexia is mediated by dysfunction of the vascular system, which is essential for maintaining perfusion and tempering inappropriate immune responses. Using transparent tissue topography, we discovered that loss of muscle vascular density precedes muscle wasting in multiple complementary tumor models, including pancreatic adenocarcinoma, colon carcinoma, lung adenocarcinoma and melanoma models. We also observed that persons suffering from cancer cachexia exhibit substantial loss of muscle vascular density. As tumors progress, increased circulating activin A remotely suppresses the expression of peroxisome proliferator-activated receptor-\u03b3 coactivator 1\u03b1 (PGC1\u03b1) in the muscle endothelium, thus inducing vascular leakage. Restoring endothelial PGC1\u03b1 activity preserved vascular density and muscle mass in tumor-bearing mice. Our study suggests that restoring muscle endothelial function could be a valuable therapeutic approach for cancer cachexia.<\/jats:p>","DOI":"10.1038\/s43018-025-00975-6","type":"journal-article","created":{"date-parts":[[2025,5,26]],"date-time":"2025-05-26T05:02:24Z","timestamp":1748235744000},"page":"1350-1369","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Skeletal muscle endothelial dysfunction through the activin A\u2013PGC1\u03b1 axis drives progression of cancer cachexia"],"prefix":"10.1038","volume":"6","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6616-2393","authenticated-orcid":false,"given":"Young-Mee","family":"Kim","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5308-4680","authenticated-orcid":false,"given":"Mark A.","family":"Sanborn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0903-6651","authenticated-orcid":false,"given":"Shaluah","family":"Vijeth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8923-1934","authenticated-orcid":false,"given":"Priyanka","family":"Gajwani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinge","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0593-3657","authenticated-orcid":false,"given":"Dahee","family":"Jung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tibor","family":"Valyi-Nagy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sreeparna","family":"Chakraborty","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5216-7086","authenticated-orcid":false,"given":"Georgina","family":"Mancinelli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2168-0124","authenticated-orcid":false,"given":"Peter T.","family":"Toth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9182-9513","authenticated-orcid":false,"given":"Evan H.","family":"Phillips","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6374-1282","authenticated-orcid":false,"given":"Paul","family":"Grippo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9037-3481","authenticated-orcid":false,"given":"Ameen A.","family":"Salahudeen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5368-5769","authenticated-orcid":false,"given":"Jooman","family":"Park","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2600-4133","authenticated-orcid":false,"given":"Su Yeon","family":"Yeon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vijayalakshmi","family":"Ananthanarayanan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5082-8012","authenticated-orcid":false,"given":"Yuwei","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1349-3759","authenticated-orcid":false,"given":"Steve Seung-Young","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Klara","family":"Valyi-Nagy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2787-9292","authenticated-orcid":false,"given":"Jalees","family":"Rehman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,5,26]]},"reference":[{"key":"975_CR1","doi-asserted-by":"publisher","first-page":"391","DOI":"10.1146\/annurev-cancerbio-030419-033642","volume":"4","author":"AK Biswas","year":"2020","unstructured":"Biswas, A. 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