{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T09:02:01Z","timestamp":1790154121110,"version":"4.0.1"},"reference-count":43,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T00:00:00Z","timestamp":1790121600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T00:00:00Z","timestamp":1790121600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J cachexia sarcopenia muscle"],"published-print":{"date-parts":[[2026,10]]},"abstract":"ABSTRACT<\/jats:title>\n \n Background<\/jats:title>\n Cancer cachexia, a debilitating syndrome characterized by muscle wasting, significantly impacts survival in gastrointestinal cancers like pancreatic cancer. Emerging evidence suggests a link between cancer cachexia and disrupted circadian rhythms in peripheral tissues, including locomotor muscles. However, circadian dysregulation in cardiorespiratory muscles\u2014whose functional decline are suspected to contribute to increased morbidity and mortality in patients experiencing cachexia\u2014remains largely unexplored.<\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n Herein, we investigated circadian gene expression patterns in cardiorespiratory muscles during cachexia using the orthotopic KPC pancreatic cancer model. To do this, circadian transcriptomes were generated from diaphragm and heart tissues collected from Sham and KPC mice every 4\u2009h over 24\u2009h, beginning on Day 12 postinoculation, which, based on our prior work, reflects the onset of cachexia in this model. Rhythmically expressed genes (REGs) (\n P<\/jats:italic>\n \n c<\/jats:italic>\n <\/jats:sub>\n <\u20090.01) were identified using the LR_rhythmicity R package, which evaluates the goodness\u2010of\u2010fit (R\n 2<\/jats:sup>\n ) to a 24\u2010h sinusoidal model of transcript oscillations. Differences in circadian patterns, including changes in amplitude, phase and basal expression, were assessed using the LR_diff R package with\n p<\/jats:italic>\n \u2009<\u20090.05.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n We found that ~60% of rhythmic genes lost their circadian rhythmicity in both tissues, with distinct shifts in gene networks. Diaphragm disruptions centred on repression in basal expression and\/or amplitude of core clock components and rest\u2010phase\u2010dependent disruptions to gene networks governing lipid and oxidative programs of metabolism and proteostasis, which were linked to an upregulation and gain of rhythmicity in inflammatory networks that peaked during the rest phase. Circadian disruptions in the heart involved loss of rhythmicity in gene networks governing cardiac function, including beta\u2010adrenergic and cAMP signalling, cellular responses to insulin and neurogenesis, with a similar, but more limited upregulation of inflammatory networks.<\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n These findings demonstrate that pancreatic cancer cachexia is associated with widespread circadian dysregulation in cardiorespiratory muscles, potentially contributing to both muscle wasting and functional decline.<\/jats:p>\n <\/jats:sec>","DOI":"10.1002\/jcsm.70383","type":"journal-article","created":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T08:09:28Z","timestamp":1790150968000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Pancreatic Cancer Disrupts Circadian Patterns of Gene Expression in Cardiorespiratory Muscles"],"prefix":"10.1002","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1653-8721","authenticated-orcid":false,"given":"Jeremy B.","family":"Ducharme","sequence":"first","affiliation":[{"name":"Department of Physical Therapy University of Florida Gainesville Florida USA"},{"name":"Myology Institute University of Florida Gainesville Florida USA"},{"name":"University of Florida Health Cancer Institute Gainesville Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0035-8219","authenticated-orcid":false,"given":"Martin M.","family":"Schonk","sequence":"additional","affiliation":[{"name":"Department of Physical Therapy University of Florida Gainesville Florida USA"},{"name":"Myology Institute University of Florida Gainesville Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8601-4080","authenticated-orcid":false,"given":"Miguel A.","family":"Gutierrez\u2010Monreal","sequence":"additional","affiliation":[{"name":"Myology Institute University of Florida Gainesville Florida USA"},{"name":"Department of Physiology and Aging University of Florida Gainesville Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6581-5882","authenticated-orcid":false,"given":"Leonardo F.","family":"Ferreira","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery Duke University School of Medicine Durham North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5791-1441","authenticated-orcid":false,"given":"Karyn A.","family":"Esser","sequence":"additional","affiliation":[{"name":"Myology Institute University of Florida Gainesville Florida USA"},{"name":"Department of Physiology and Aging University of Florida Gainesville Florida 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 Florida USA"},{"name":"Myology Institute University of Florida Gainesville Florida USA"},{"name":"University of Florida Health Cancer Institute Gainesville Florida 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 Florida USA"},{"name":"Myology Institute University of Florida Gainesville Florida USA"},{"name":"University of Florida Health Cancer Institute Gainesville Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,23]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"crossref","first-page":"793","DOI":"10.1016\/j.clnu.2008.06.013","article-title":"Cachexia: A New Definition","volume":"27","author":"Evans W. J.","year":"2008","journal-title":"Clinical Nutrition"},{"key":"e_1_2_8_3_1","doi-asserted-by":"crossref","DOI":"10.1155\/2011\/601434","article-title":"Cancer Cachexia: Mechanisms and Clinical Implications","volume":"2011","author":"Donohoe C. L.","year":"2011","journal-title":"Gastroenterology Research and Practice"},{"key":"e_1_2_8_4_1","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1002\/jcsm.12675","article-title":"The Regulatory Approval of Anamorelin for Treatment of Cachexia in Patients With Non\u2010Small Cell Lung Cancer, Gastric Cancer, Pancreatic Cancer, and Colorectal Cancer in Japan: Facts and Numbers","volume":"12","author":"Wakabayashi H.","year":"2021","journal-title":"Journal of Cachexia, Sarcopenia and Muscle"},{"key":"e_1_2_8_5_1","doi-asserted-by":"crossref","first-page":"2291","DOI":"10.1056\/NEJMoa2409515","article-title":"Ponsegromab for the Treatment of Cancer Cachexia","volume":"391","author":"Groarke J. D.","year":"2024","journal-title":"New England Journal of Medicine"},{"key":"e_1_2_8_6_1","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1186\/s41606-017-0019-2","article-title":"A Circadian Based Inflammatory Response \u2013 Implications for Respiratory Disease and Treatment","volume":"1","author":"Comas M.","year":"2017","journal-title":"Sleep Science and Practice"},{"key":"e_1_2_8_7_1","first-page":"127","volume-title":"Handbook of Experimental Pharmacology","author":"Marcheva B.","year":"2013"},{"key":"e_1_2_8_8_1","doi-asserted-by":"crossref","DOI":"10.1093\/jncics\/pky043","article-title":"Skeletal Muscle Fibrosis in Pancreatic Cancer Patients With Respect to Survival","volume":"2","author":"Judge S. M.","year":"2018","journal-title":"JNCI Cancer Spectr"},{"key":"e_1_2_8_9_1","doi-asserted-by":"crossref","first-page":"820","DOI":"10.1002\/jcsm.12550","article-title":"Distinct Cachexia Profiles in Response to Human Pancreatic Tumours in Mouse Limb and Respiratory Muscle","volume":"11","author":"Nosacka R. L.","year":"2020","journal-title":"Journal of Cachexia, Sarcopenia and Muscle"},{"key":"e_1_2_8_10_1","doi-asserted-by":"crossref","DOI":"10.7717\/peerj.4327","article-title":"Evidence for Widespread Dysregulation of Circadian Clock Progression in Human Cancer","volume":"6","author":"Shilts J.","year":"2018","journal-title":"PeerJ"},{"key":"e_1_2_8_11_1","doi-asserted-by":"crossref","first-page":"34128","DOI":"10.18632\/oncotarget.16699","article-title":"Remote Reprogramming of Hepatic Circadian Transcriptome by Breast Cancer","volume":"8","author":"Hojo H.","year":"2017","journal-title":"Oncotarget"},{"key":"e_1_2_8_12_1","doi-asserted-by":"crossref","first-page":"896","DOI":"10.1016\/j.cell.2016.04.039","article-title":"Lung Adenocarcinoma Distally Rewires Hepatic Circadian Homeostasis","volume":"165","author":"Masri S.","year":"2016","journal-title":"Cell"},{"key":"e_1_2_8_13_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.celrep.2025.115689","article-title":"Cancer\u2010Induced FOXP1 Disrupts and Reprograms Skeletal\u2010Muscle Circadian Transcription in Cachexia","volume":"44","author":"Ducharme J. B.","year":"2025","journal-title":"Cell Reports"},{"key":"e_1_2_8_14_1","doi-asserted-by":"crossref","first-page":"1823","DOI":"10.1016\/j.ajpath.2024.06.008","article-title":"Cardiac Atrophy, Dysfunction, and Metabolic Impairments: A Cancer\u2010Induced Cardiomyopathy Phenotype","volume":"194","author":"Ogilvie L. M.","year":"2024","journal-title":"American Journal of Pathology"},{"key":"e_1_2_8_15_1","doi-asserted-by":"crossref","first-page":"824","DOI":"10.1002\/jcsm.12225","article-title":"Establishment and Characterization of a Novel Murine Model of Pancreatic Cancer Cachexia","volume":"8","author":"Michaelis K. A.","year":"2017","journal-title":"Journal of Cachexia, Sarcopenia and Muscle"},{"key":"e_1_2_8_16_1","doi-asserted-by":"crossref","first-page":"849","DOI":"10.1016\/j.trecan.2018.10.001","article-title":"Cancer Cachexia: More Than Skeletal Muscle Wasting","volume":"4","author":"Schmidt S. F.","year":"2018","journal-title":"Trends Cancer"},{"key":"e_1_2_8_17_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s42003-023-04902-2","article-title":"Blocking Muscle Wasting via Deletion of the Muscle\u2010Specific E3 Ligase MuRF1 Impedes Pancreatic Tumor Growth","volume":"6","author":"Neyroud D.","year":"2023","journal-title":"Communications Biology"},{"key":"e_1_2_8_18_1","doi-asserted-by":"crossref","DOI":"10.1002\/jcsm.13668","article-title":"Local Inflammation Precedes Diaphragm Wasting and Fibrotic Remodelling in a Mouse Model of Pancreatic Cancer","volume":"16","author":"Neyroud D.","year":"2025","journal-title":"Journal of Cachexia, Sarcopenia and Muscle"},{"key":"e_1_2_8_19_1","doi-asserted-by":"crossref","first-page":"C1","DOI":"10.1152\/ajpcell.00701.2024","article-title":"Role of Myofiber\u2010Specific FoxP1 in Pancreatic Cancer\u2010Induced Muscle Wasting","volume":"328","author":"Schonk M. 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P.","year":"2022","journal-title":"Nature Communications"},{"key":"e_1_2_8_29_1","doi-asserted-by":"crossref","first-page":"36828","DOI":"10.1074\/jbc.M404927200","article-title":"ROR\u03b1 Regulates the Expression of Genes Involved in Lipid Homeostasis in Skeletal Muscle Cells: Caveolin\u20103 and CPT\u20101 Are Direct Targets of ROR *","volume":"279","author":"Lau P.","year":"2004","journal-title":"Journal of Biological Chemistry"},{"key":"e_1_2_8_30_1","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1002\/jcsm.13432","article-title":"ROR\u03b1\u2013GABP\u2013TFAM Axis Alleviates Myosteatosis With Fatty Atrophy Through Reinforcement of Mitochondrial Capacity","volume":"15","author":"Kim H.","year":"2024","journal-title":"Journal of Cachexia, Sarcopenia and Muscle"},{"key":"e_1_2_8_31_1","doi-asserted-by":"crossref","DOI":"10.1038\/s41598-017-14596-2","article-title":"Rev\u2010Erb\u2010\u03b1 Regulates Atrophy\u2010Related Genes to Control Skeletal Muscle Mass","volume":"7","author":"Mayeuf\u2010Louchart A.","year":"2017","journal-title":"Scientific Reports"},{"key":"e_1_2_8_32_1","doi-asserted-by":"crossref","first-page":"1039","DOI":"10.1038\/nm.3213","article-title":"Rev\u2010Erb\u2010\u03b1 Modulates Skeletal Muscle Oxidative Capacity by Regulating Mitochondrial Biogenesis and Autophagy","volume":"19","author":"Woldt E.","year":"2013","journal-title":"Nature Medicine"},{"key":"e_1_2_8_33_1","doi-asserted-by":"crossref","first-page":"R1058","DOI":"10.1152\/ajpregu.00010.2020","article-title":"Circadian Clock Genes and Respiratory Neuroplasticity Genes Oscillate in the Phrenic Motor System","volume":"318","author":"Kelly M. N.","year":"2020","journal-title":"American Journal of Physiology. Regulatory, Integrative and Comparative Physiology"},{"key":"e_1_2_8_34_1","doi-asserted-by":"crossref","first-page":"4887","DOI":"10.1007\/s00018-019-03148-8","article-title":"Proinflammatory NFkB Signalling Promotes Mitochondrial Dysfunction in Skeletal Muscle in Response to Cellular Fuel Overloading","volume":"76","author":"Nisr R. B.","year":"2019","journal-title":"Cellular and Molecular Life Sciences"},{"key":"e_1_2_8_35_1","first-page":"533","article-title":"Importance of Functional and Metabolic Impairments in the Characterization of the C\u201026 Murine Model of Cancer Cachexia","volume":"5","author":"Murphy K. 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