{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T01:52:54Z","timestamp":1793065974005,"version":"4.5.0"},"posted":{"date-parts":[[2025,9,5]]},"group-title":"Cancer Biology","reference-count":45,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,9,5]],"date-time":"2025-09-05T00:00:00Z","timestamp":1757030400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"name":"National Cancer Institute","award":["P01 CA236778-01A1"],"award-info":[{"award-number":["P01 CA236778-01A1"]}]},{"name":"National Cancer Institute","award":["R01CA257452"],"award-info":[{"award-number":["R01CA257452"]}]},{"name":"National Cancer Institute","award":["T32 CA254888"],"award-info":[{"award-number":["T32 CA254888"]}]},{"name":"National Cancer Institute","award":["1L70CA284463-01"],"award-info":[{"award-number":["1L70CA284463-01"]}]},{"name":"National Cancer Institute","award":["P30 CA069533"],"award-info":[{"award-number":["P30 CA069533"]}]},{"name":"National Cancer Institute","award":["P30 CA082709"],"award-info":[{"award-number":["P30 CA082709"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,9,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Skeletal muscle loss in pancreatic cancer is a significant cause of morbidity and mortality for patients. In order to understand myocytes changes we examined myonuclei- and myofiber-specific dynamics during pancreatic cancer cachexia progression. Single-nucleus RNA-seq was used to interrogate myonuclear gene expression, and RNAscope and immunofluorescence characterized myofiber-specific changes. Bulk RNA-seq of skeletal muscle provided a whole-muscle transcriptomic profile. Cachexia induces a progressive loss of muscle differentiation factor\n                  <jats:italic>Maf<\/jats:italic>\n                  and its target\n                  <jats:italic>Myh4<\/jats:italic>\n                  , accompanied by increased expression of\n                  <jats:italic>Myh1<\/jats:italic>\n                  and\n                  <jats:italic>Myh2<\/jats:italic>\n                  . This myofiber dedifferentiation occurs without evidence for fiber type shifting, regeneration, or proliferation. Single-nuclei analysis reveals global shifts in myofiber gene expression identity including the identification of a cachexia only myonuclear subpopulation. Cachexia gene expression was not restricted solely to this PDAC-specific myonuclear subpopulation and did not overlap with\n                  <jats:italic>Myh1<\/jats:italic>\n                  and\n                  <jats:italic>Myh2<\/jats:italic>\n                  expressing myonuclei early in cachexia. Altogether, PDAC cachexia elicits distinct transcriptional responses across different myonuclear populations. These results reveal population-specific heterogeneity in cachexia gene activation, rather than a uniform upregulation of cachexia mediators across muscle tissue. Our data suggest that myonuclei fate occurs prior to overt muscle wasting when cachexia gene expression only modestly overlaps with differentiation factors, with a strong association after irreversible muscle wasting. These findings explain the challenge of effectively targeting skeletal muscle wasting in cancer cachexia requires addressing the changing cell population induced through non overlapping mechanisms.\n                <\/jats:p>","DOI":"10.1101\/2025.09.01.673500","type":"posted-content","created":{"date-parts":[[2025,9,5]],"date-time":"2025-09-05T16:30:12Z","timestamp":1757089812000},"source":"Crossref","is-referenced-by-count":1,"title":["Pancreatic Cancer Induces Population-Specific Switching of Myosin Isoforms and Discrete Activation of Cachexia Genes in Skeletal Muscle Myocytes"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4525-9820","authenticated-orcid":false,"given":"Brittany R.","family":"Counts","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sephora","family":"Jean","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Omnia","family":"Gaafer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara K.","family":"Ota","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iishaan","family":"Inabathini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tingbo","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Denis C.","family":"Guttridge","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael C.","family":"Ostrowski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4864-6380","authenticated-orcid":false,"given":"Leonidas G.","family":"Koniaris","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sha","family":"Cao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8176-5747","authenticated-orcid":false,"given":"Hyun C.","family":"Roh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7872-0540","authenticated-orcid":false,"given":"Teresa A.","family":"Zimmers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025090914202013000_2025.09.01.673500v1.1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21820"},{"key":"2025090914202013000_2025.09.01.673500v1.2","doi-asserted-by":"publisher","DOI":"10.21037\/jgo.2017.11.10"},{"key":"2025090914202013000_2025.09.01.673500v1.3","doi-asserted-by":"crossref","unstructured":"Dunne RF , Crawford J , Smoyer KE , McRae TD , Rossulek MI , Revkin JH , Tarasenko LC , Bonomi PD : The mortality burden of cachexia or weight loss in patients with colorectal or pancreatic cancer: A systematic literature review. 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