{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T16:40:42Z","timestamp":1790354442246,"version":"4.1.0"},"reference-count":41,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2025,4,4]],"date-time":"2025-04-04T00:00:00Z","timestamp":1743724800000},"content-version":"vor","delay-in-days":3,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,4,1]],"date-time":"2025-04-01T00:00:00Z","timestamp":1743465600000},"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":[[2025,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Cachexia is a severe form of muscle wasting disorder particularly observed in patients with advanced cancer. The absence of effective strategies to ameliorate cachexia indicates our poor understanding of the mechanisms of cachexia. By employing system\u2010wide approaches, we investigated molecular mechanisms underlying cancer secreted pro\u2010inflammatory cytokine\u2010induced cachexia (CIC).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>As cellular model systems, we employed mouse satellite stem cell\u2010derived primary muscle cells, mouse C2C12 myoblast progenitor cell\u2010derived myotubes, and neonatal rat cardiomyocytes. We induced CIC by incubating striated muscle cells with pro\u2010inflammatory cytokines TNF\u2010\u03b1 and IFN\u2010\u03b3. To understand the physiological effects of CIC, we probed the contractile properties of muscle cells following electrical stimulation and measured intracellular calcium transients. Effects of CIC on sarcomere organization were monitored by confocal microscopy. Large\u2010scale quantitative proteomics and RNA sequencing assays enabled us to examine molecular mechanisms underlying CIC. Using chromatin immunoprecipitation experiments, chromatin signalling and modulation of epigenetic marks on muscle\u2010specific genes were investigated.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Here, we observed a drastic loss of striated muscle cell contraction in CIC, primarily, due to acutely disorganized sarcomere structures and impeded calcium handling process. In calcium transients, the extent of calcium (Ca\n                      <jats:sup>2+<\/jats:sup>\n                      ) release, as indicated by the calcium amplitude during the excitation\u2013contraction coupling (ECC) process, was reduced (19.6\u2009\u00b1\u20092.35% in control to 8.6\u2009\u00b1\u20091.52% in CIC,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20094.8\u2009*\u200910\n                      <jats:sup>\u221211<\/jats:sup>\n                      ). Kinetics of calcium transients, i.e., the Ca\n                      <jats:sup>2+<\/jats:sup>\n                      release rate (26\u2009\u00b1\u20090.5\u2009ms in control to 29\u2009\u00b1\u20095.1\u2009ms in CIC, median\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.014), and calcium re\u2010uptake rate (137\u2009\u00b1\u200913\u2009ms in control to 185\u2009\u00b1\u200924\u2009ms in CIC,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.032) were both prolonged. Proteomic analysis showed altered proteostasis in CIC, particularly related to sarcomere and sarcoplasmic reticulum (SR). Transcriptomic analysis unravelled upstream deregulation of global transcriptional events for sarcomeric and SR genes. Mechanistically, chromatin loading of transcriptionally active RNA Polymerase II on muscle\u2010specific genes, including\n                      <jats:italic>Myh1<\/jats:italic>\n                      and\n                      <jats:italic>Atp2a1<\/jats:italic>\n                      , was impeded. This was due to diminished transcriptionally active epigenetic marks H3K4 trimethylation on\n                      <jats:italic>Myh1<\/jats:italic>\n                      and\n                      <jats:italic>Atp2a1<\/jats:italic>\n                      , resulted in lower transcriptional activity of these muscle\u2010specific genes in CIC and ultimately reduced MyHC\u2010IId molecular motor protein and SERCA1 protein levels.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our top\u2010down approach elucidated that the altered transcriptional mechanism and proteomic state perturbed functionally related machinery responsible for calcium handling and sarcomere organization in CIC. Knowledge of the underlying cause of muscle mass loss and compromised muscle function is key for developing therapeutic solutions to ameliorate cachectic conditions.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/jcsm.13776","type":"journal-article","created":{"date-parts":[[2025,4,5]],"date-time":"2025-04-05T09:15:48Z","timestamp":1743844548000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Calcium Handling Machinery and Sarcomere Assembly are Impaired Through Multipronged Mechanisms in Cancer Cytokine\u2010Induced Cachexia"],"prefix":"10.1002","volume":"16","author":[{"given":"Luis\u00a0Vincens","family":"Gand","sequence":"first","affiliation":[{"name":"Institute of Molecular and Cell Physiology Hannover Medical School  Hannover Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"Lanzuolo","sequence":"additional","affiliation":[{"name":"Istituto Nazionale Genetica Molecolare \u2018Romeo ed Enrica Invernizzi\u2019  Milan Italy"},{"name":"Institute of Biomedical Technologies National Research Council  Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mugeng","family":"Li","sequence":"additional","affiliation":[{"name":"Institute of Molecular and Cell Physiology Hannover Medical School  Hannover Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"Rosti","sequence":"additional","affiliation":[{"name":"Istituto Nazionale Genetica Molecolare \u2018Romeo ed Enrica Invernizzi\u2019  Milan Italy"},{"name":"Institute of Biomedical Technologies National Research Council  Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalie","family":"Weber","sequence":"additional","affiliation":[{"name":"Institute of Molecular and Translational Therapeutic Strategies Hannover Medical School  Hannover Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongchao","family":"Lu","sequence":"additional","affiliation":[{"name":"Institute of Molecular and Translational Therapeutic Strategies Hannover Medical School  Hannover Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"B\u00e4r","sequence":"additional","affiliation":[{"name":"Institute of Molecular and Translational Therapeutic Strategies Hannover Medical School  Hannover Germany"},{"name":"Fraunhofer Institute for Toxicology and Experimental Medicine (ITEM) Fraunhofer Cluster of Excellence Immune\u2010Mediated Diseases (CIMD)  Hannover Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Thum","sequence":"additional","affiliation":[{"name":"Institute of Molecular and Translational Therapeutic Strategies Hannover Medical School  Hannover 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