{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T18:30:57Z","timestamp":1793298657725,"version":"4.5.0"},"posted":{"date-parts":[[2025,9,18]]},"group-title":"Cell Biology","reference-count":78,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,9,18]],"date-time":"2025-09-18T00:00:00Z","timestamp":1758153600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000069","name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases","doi-asserted-by":"crossref","award":["AR081487"],"award-info":[{"award-number":["AR081487"]}],"id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"crossref"}]},{"name":"National Cancer Institute","award":["CA294365"],"award-info":[{"award-number":["CA294365"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,9,17]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>Cachexia is a debilitating syndrome marked by progressive skeletal muscle wasting, commonly affecting cancer patients, particularly those with pancreatic cancer. Despite its clinical significance, the molecular mechanisms underlying cancer cachexia remain poorly understood. In this study, we utilized single-nucleus RNA sequencing (snRNA-seq) and bulk RNA-seq, complemented by biochemical and histological analyses, to investigate molecular alterations in the skeletal muscle of the KPC mouse model of pancreatic cancer cachexia. Our findings demonstrate that KPC tumor growth induces myofiber-specific changes in the expression of genes involved in proteolytic pathways, mitochondrial biogenesis, and angiogenesis. Notably, tumor progression enhances the activity of specific transcription factors that regulate the mTORC1 signaling pathway, along with genes involved in translational initiation and ribosome biogenesis. Skeletal muscle-specific, inducible inhibition of mTORC1 activity further exacerbates muscle loss in tumor-bearing mice, highlighting its protective role in maintaining muscle mass. Additionally, we uncovered novel intercellular signaling networks within the skeletal muscle microenvironment during pancreatic cancer-induced cachexia. Together, these results reveal previously unrecognized molecular mechanisms that regulate skeletal muscle homeostasis and identify potential therapeutic targets for the treatment of pancreatic cancer-associated cachexia.<\/jats:p>","DOI":"10.1101\/2025.09.15.676415","type":"posted-content","created":{"date-parts":[[2025,9,18]],"date-time":"2025-09-18T08:20:16Z","timestamp":1758183616000},"source":"Crossref","is-referenced-by-count":1,"title":["Fiber-type vulnerability and proteostasis reprogramming in skeletal muscle during pancreatic cancer cachexia"],"prefix":"10.64898","author":[{"given":"Bowen","family":"Xu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aniket S.","family":"Joshi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meiricris","family":"Tomaz da Silva","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silin","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8571-2848","authenticated-orcid":false,"given":"Ashok","family":"Kumar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025092202503015000_2025.09.15.676415v1.1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2012.06.011"},{"key":"2025092202503015000_2025.09.15.676415v1.2","doi-asserted-by":"publisher","DOI":"10.1186\/s13045-023-01454-0"},{"key":"2025092202503015000_2025.09.15.676415v1.3","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(10)70218-7"},{"key":"2025092202503015000_2025.09.15.676415v1.4","doi-asserted-by":"publisher","DOI":"10.1038\/nrc3829"},{"key":"2025092202503015000_2025.09.15.676415v1.5","doi-asserted-by":"publisher","DOI":"10.3390\/nu12061543"},{"key":"2025092202503015000_2025.09.15.676415v1.6","doi-asserted-by":"publisher","DOI":"10.1634\/theoncologist.2018-0266"},{"key":"2025092202503015000_2025.09.15.676415v1.7","doi-asserted-by":"publisher","DOI":"10.1038\/s41416-021-01301-4"},{"key":"2025092202503015000_2025.09.15.676415v1.8","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00016.2008"},{"key":"2025092202503015000_2025.09.15.676415v1.9","doi-asserted-by":"publisher","DOI":"10.1038\/s41568-020-0251-4"},{"key":"2025092202503015000_2025.09.15.676415v1.10","doi-asserted-by":"crossref","unstructured":"Beltra, M. , Pin, F. , Ballaro, R. , Costelli, P. , and Penna, F . 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