{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T10:03:26Z","timestamp":1784887406353,"version":"3.55.0"},"reference-count":47,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2026,5,9]],"date-time":"2026-05-09T00:00:00Z","timestamp":1778284800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,5,9]],"date-time":"2026-05-09T00:00:00Z","timestamp":1778284800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100018202","name":"Artificial Intelligence Research Center","doi-asserted-by":"publisher","award":["ID 24762"],"award-info":[{"award-number":["ID 24762"]}],"id":[{"id":"10.13039\/100018202","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":[[2026,6]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Cancer cachexia (CC) is a highly debilitating syndrome characterized by loss of body and muscle weight affecting most advanced cancer patients. The receptor for advanced glycation end\u2010products (RAGE) is expressed by several cell types and sustains the inflammatory response in acute and chronic diseases. Total ablation of RAGE (\n                      <jats:italic>Ager<\/jats:italic>\n                      <jats:sup>\u2212\/\u2212<\/jats:sup>\n                      mice) translates into restrained CC and increased survival in tumour\u2010bearing mice. RAGE, which is not expressed in adult healthy myofibres, is re\u2010expressed in atrophying myofibres in cancer conditions. However, the specific contribution of muscular RAGE to CC was unknown.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Using an HSA\/Cre\u2010\n                      <jats:italic>loxP<\/jats:italic>\n                      system, we generated a tamoxifen\u2010inducible conditional\n                      <jats:italic>Ager<\/jats:italic>\n                      <jats:sup>mKO<\/jats:sup>\n                      mouse model in which RAGE is selectively ablated in myofibres. Tamoxifen\u2010treated\n                      <jats:italic>Ager<\/jats:italic>\n                      <jats:sup>mKO<\/jats:sup>\n                      ,\n                      <jats:italic>Ager<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>flox<\/jats:italic>\n                      <\/jats:sup>\n                      and\n                      <jats:italic>Ager<\/jats:italic>\n                      <jats:sup>\u2212\/\u2212<\/jats:sup>\n                      mice were subcutaneously injected with Lewis lung carcinoma (LLC) cells, and body changes and survival were monitored until 25\u2009dpi, when histological, molecular and proteomic analyses were performed in tumour\u2010bearing and control mice. Muscle samples of pre\u2010cachectic and cachectic pancreatic cancer patients were analysed to validate the results.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Compared with LLC\u2010\n                      <jats:italic>Ager<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>flox<\/jats:italic>\n                      <\/jats:sup>\n                      mice, LLC\u2010\n                      <jats:italic>Ager<\/jats:italic>\n                      <jats:sup>mKO<\/jats:sup>\n                      mice showed reduced (7.5% [\n                      <jats:italic>p\u2009=<\/jats:italic>\n                      \u20090.004] vs. 15.1% [\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.0001]) body weight loss, no significant reduction of hind\u2010limb muscle mass and strength and myofibre cross\u2010sectional areas, increased survival (69.2% vs. 42.9% mice alive at 25\u2009dpi) and restrained muscle and serum pro\u2010inflammatory factors. Mechanistically,\n                      <jats:italic>Ager<\/jats:italic>\n                      <jats:sup>mKO<\/jats:sup>\n                      muscles resist cancer\u2010induced atrophy by maintaining an active Akt\u2010GSK\u20103\u03b2\u2010PGC\u20101\u03b1 pathway, and increasing the synthesis of myosin heavy chain (MyHC)\u2010I and \u2010IIa (71.8% [\n                      <jats:italic>p\u2009=<\/jats:italic>\n                      \u20090.008] and 73.9% [\n                      <jats:italic>p\u2009=<\/jats:italic>\n                      \u20090.002] increase, respectively) along with a 76.3% (\n                      <jats:italic>p\u2009=<\/jats:italic>\n                      \u20090.008) increase in hybrid MyHC\u2010I\/IIa myofibres. Distinct proteomic signatures characterize muscles of tumour\u2010bearing mice in dependence on RAGE expression, supporting a protective effect of RAGE ablation in muscles. LLC\/\n                      <jats:italic>Ager<\/jats:italic>\n                      <jats:sup>mKO<\/jats:sup>\n                      muscles showed increased amounts of several enzymes involved in glycolysis and glucose catabolism, typical of Warburg metabolism. Noteworthy, muscles of pre\u2010cachectic and cachectic cancer patients showed ~3\u2010fold increase (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.05) in RAGE amounts and reduced Akt\u2010GSK\u20103\u03b2\u2010PGC\u20101\u03b1 pathway, compared with healthy control subjects.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our data provide evidence that RAGE engagement at myofibre level drives loss of body and muscle weights and inflammation in cancer conditions. RAGE ablation in muscles confers resistance to CC through myofibre remodeling and glycolytic reprogramming. On the clinical side, the overexpression of RAGE is an early event in muscles of cancer patients, suggesting a role for RAGE in the onset of the cachectic syndrome. Thus, the molecular targeting of RAGE might be useful to counteract cachexia and prolong survival in cancer patients.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/jcsm.70302","type":"journal-article","created":{"date-parts":[[2026,5,9]],"date-time":"2026-05-09T09:42:17Z","timestamp":1778319737000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["RAGE Re\u2010Expressed at Myofibre Level Drives Muscle Wasting in Cancer Conditions"],"prefix":"10.1002","volume":"17","author":[{"given":"Sara","family":"Chiappalupi","sequence":"first","affiliation":[{"name":"Department of Medicine and Surgery University of Perugia  Perugia Italy"},{"name":"Interuniversity Institute of Myology (IIM)  Perugia Italy"},{"name":"Consorzio Interuniversitario Biotecnologie (CIB)  Trieste 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