{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T11:27:38Z","timestamp":1784719658278,"version":"3.55.0"},"reference-count":74,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2021,2,1]],"date-time":"2021-02-01T00:00:00Z","timestamp":1612137600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001711","name":"Schweizerischer Nationalfonds zur F\u00f6rderung der Wissenschaftlichen Forschung","doi-asserted-by":"publisher","award":["P400PM_180814"],"award-info":[{"award-number":["P400PM_180814"]}],"id":[{"id":"10.13039\/501100001711","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000069","name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases","doi-asserted-by":"publisher","award":["R01AR060209"],"award-info":[{"award-number":["R01AR060209"]}],"id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J cachexia sarcopenia muscle"],"published-print":{"date-parts":[[2021,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Skeletal muscle wasting is a devastating consequence of cancer that affects up to 80% of cancer patients and associates with reduced survival. Herein, we investigated the biological significance of Forkhead box P1 (FoxP1), a transcriptional repressor that we demonstrate is up\u2010regulated in skeletal muscle in multiple models of cancer cachexia and in cachectic cancer patients.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Inducible, skeletal muscle\u2010specific FoxP1 over\u2010expressing (FoxP1<jats:sup>iSkmTg\/Tg<\/jats:sup>) mice were generated through crossing conditional <jats:italic>Foxp1a<\/jats:italic> transgenic mice with HSA\u2010MCM mice that express tamoxifen\u2010inducible Cre recombinase under control of the skeletal muscle actin promoter. To determine the requirement of FoxP1 for cancer\u2010induced skeletal muscle wasting, FoxP1\u2010shRNA was packaged and targeted to muscles using AAV9 delivery prior to inoculation of mice with Colon\u201026 Adenocarcinoma (C26) cells.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Up\u2010regulation of FoxP1 in adult skeletal muscle was sufficient to induce features of cachexia, including 15% reduction in body mass (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05), and a 16\u201327% reduction in skeletal muscle mass (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05) that was characterized by a 20% reduction in muscle fibre cross\u2010sectional area of type IIX\/B muscle fibres (<jats:italic>P<\/jats:italic>\u00a0=\u00a00.020). Skeletal muscles from FoxP1<jats:sup>iSkmTg\/Tg<\/jats:sup> mice also showed significant damage and myopathy characterized by the presence of centrally nucleated myofibres, extracellular matrix expansion, and were 19\u201326% weaker than controls (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05). Transcriptomic analysis revealed FoxP1 as a potent transcriptional repressor of skeletal muscle gene expression, with enrichment of pathways related to skeletal muscle structure and function, growth signalling, and cell quality control. Because FoxP1 functions, at least in part, as a transcriptional repressor through its interaction with histone deacetylase proteins, we treated FoxP1<jats:sup>iSkmTg\/Tg<\/jats:sup> mice with Trichostatin A, and found that this completely prevented the loss of muscle mass (<jats:italic>p<\/jats:italic>\u00a0=\u00a00.007) and fibre atrophy (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001) in the <jats:italic>tibialis anterior<\/jats:italic>. In the context of cancer, FoxP1 knockdown blocked the cancer\u2010induced repression of myocyte enhancer factor 2 (MEF2)\u2010target genes critical to muscle differentiation and repair, improved muscle ultrastructure, and attenuated muscle fibre atrophy by 50% (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>In summary, we identify FoxP1 as a novel repressor of skeletal muscle gene expression that is increased in cancer cachexia, whose up\u2010regulation is sufficient to induce skeletal muscle wasting and weakness, and required for the normal wasting response to cancer.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcsm.12666","type":"journal-article","created":{"date-parts":[[2021,2,3]],"date-time":"2021-02-03T07:45:00Z","timestamp":1612338300000},"page":"421-442","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["FoxP1 is a transcriptional repressor associated with cancer cachexia that induces skeletal muscle wasting and weakness"],"prefix":"10.1002","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5886-802X","authenticated-orcid":false,"given":"Daria","family":"Neyroud","sequence":"first","affiliation":[{"name":"Department of Physical Therapy University of Florida  Gainesville FL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8347-9501","authenticated-orcid":false,"given":"Rachel L.","family":"Nosacka","sequence":"additional","affiliation":[{"name":"Department of Physical Therapy University of Florida  Gainesville FL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4562-0508","authenticated-orcid":false,"given":"Chandler S.","family":"Callaway","sequence":"additional","affiliation":[{"name":"Department of Physical Therapy University of Florida  Gainesville FL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jose G.","family":"Trevino","sequence":"additional","affiliation":[{"name":"Department of Surgery University of Florida  Gainesville FL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Microbiology University of Alabama at Birmingham  Birmingham AL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3974-0247","authenticated-orcid":false,"given":"Sarah M.","family":"Judge","sequence":"additional","affiliation":[{"name":"Department of Physical Therapy University of Florida  Gainesville FL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4488-291X","authenticated-orcid":false,"given":"Andrew R.","family":"Judge","sequence":"additional","affiliation":[{"name":"Department of Physical Therapy University of Florida  Gainesville FL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,2]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrclinonc.2012.209"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0149-2918(05)80001-3"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/90.9.675"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.30950"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11605-008-0505-z"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1530\/JOE-15-0170"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrdp.2017.105"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.13-240580"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-16-0337"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/emboj.2011.292"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-02347-2"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0087776"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.11-189977"},{"key":"e_1_2_10_15_1","first-page":"R707","article-title":"Janus kinase inhibition prevents cancer\u2010 and myocardial infarction\u2010mediated diaphragm muscle weakness in mice. 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