{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T01:09:34Z","timestamp":1773018574337,"version":"3.50.1"},"reference-count":40,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2026,2,15]],"date-time":"2026-02-15T00:00:00Z","timestamp":1771113600000},"content-version":"vor","delay-in-days":14,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,2,1]],"date-time":"2026-02-01T00:00:00Z","timestamp":1769904000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["HL\u2010121500"],"award-info":[{"award-number":["HL\u2010121500"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001826","name":"ZonMw","doi-asserted-by":"publisher","award":["09120011910004"],"award-info":[{"award-number":["09120011910004"]}],"id":[{"id":"10.13039\/501100001826","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000069","name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases","doi-asserted-by":"publisher","award":["R01AR084850"],"award-info":[{"award-number":["R01AR084850"]}],"id":[{"id":"10.13039\/100000069","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":[[2026,2]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Diaphragm weakness frequently develops in critically ill patients and is explained by a combination of atrophy and myofiber dysfunction. Myofibers are large syncytial cells maintained by a population of myonuclei, which provide gene transcripts to a finite fiber volume, termed the myonuclear domain. Myonuclear number is a determinant of transcriptional capacity and therefore critical for diaphragm and peripheral muscle regeneration after critical illness. Changes in myonuclear number in myofibers undergoing atrophy have not been investigated in mechanically ventilated ICU patients, but they are of potential clinical importance. Our objective was to investigate if and how myonuclear number changes in the diaphragm of mechanically ventilated ICU patients and whether changes are associated with myofiber atrophy and clinical parameters.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We used a combination of transcriptomics, immunohistochemistry and confocal microscopy to study myonuclear alterations in the diaphragm and quadriceps biopsies from mechanically ventilated ICU patients (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u200924) and non\u2010critically ill patients (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u200910).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Compared to control patients, myonuclear number and myonuclear domain were reduced in critically ill patients with diaphragm myofiber atrophy (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u200914) (myonuclear number per mm of 133 [92\u2013183] vs. 92 [83\u2013105],\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.03 (slow myofibers) and 149 [118\u2013189] vs. 88 [69\u2013109],\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.004 (fast myofibers); myonuclear domain size was 44 [34\u201351] vs. 29 pL,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.004 (slow myofibers) and 41 [39\u201348] vs. 27 pL,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.001 (fast myofibers) of control patients and ICU patients with atrophy, respectively). Increased intrinsic apoptotic pathway activation was identified as a mechanism underlying myonuclear removal (percentage of apoptotic myonuclei of 0.64 [0.60\u20130.84] and 0.95 [0.84\u20131.2],\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.015 and increased percentage of activated caspase\u20103 positive myonuclei of 2,5 [1.6\u20133.3] vs. 5.7 [4.3\u201311],\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.001 in control patients and ICU patients with atrophy, respectively). Total transcriptional activity in myofibers decreased with myonuclear loss (RNA\u2010Pol\u20102 Ser5 fluorescence intensity per fibre of 2.6 [2.2\u20133.3] vs. 5.8 [3.1\u20136.7] AU,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.036 in control patients and ICU patients with atrophy, respectively). Furthermore, muscle stem cell number was reduced in the patients with diaphragm atrophy (PAX7 positive nuclei per myofiber of 0.10 [0.09\u20130.11] vs. 0.05 [0.04\u20130.07],\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.002 in control patients and ICU patients with atrophy, respectively). No correlation was found between myonuclear loss and duration or mode of mechanical ventilation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>We identified myonuclear loss due to intrinsic apoptotic pathway activation as a potential mechanism underlying diaphragm atrophy in mechanically ventilated patients. The loss of myonuclei may contribute to impaired regeneration of myofibers after critical illness. Duration and mode of mechanical ventilation are not the major drivers of these modifications.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/jcsm.70228","type":"journal-article","created":{"date-parts":[[2026,2,16]],"date-time":"2026-02-16T06:34:08Z","timestamp":1771223648000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Loss of Myonuclei and Transcriptional Activity During Diaphragm Atrophy in Critically Ill Patients"],"prefix":"10.1002","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5154-7311","authenticated-orcid":false,"given":"Wout\u00a0J.","family":"Claassen","sequence":"first","affiliation":[{"name":"Department of Physiology Amsterdam UMC, location VUmc  Amsterdam the Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marloes","family":"van den Berg","sequence":"additional","affiliation":[{"name":"Department of Physiology Amsterdam UMC, location VUmc  Amsterdam the Netherlands"},{"name":"Department of Cellular and Molecular Medicine University of Arizona  Tucson Arizona USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhong\u00a0Hua","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of Physiology Amsterdam UMC, location VUmc  Amsterdam the Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rianne.\u00a0J.","family":"Baelde","sequence":"additional","affiliation":[{"name":"Department of Physiology Amsterdam UMC, location VUmc  Amsterdam the Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sylvia","family":"Bogaards","sequence":"additional","affiliation":[{"name":"Department of Physiology Amsterdam UMC, location VUmc  Amsterdam the Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luuk","family":"Bonis","sequence":"additional","affiliation":[{"name":"Department of Physiology Amsterdam UMC, location VUmc  Amsterdam the Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Heleen","family":"Hakkeling","sequence":"additional","affiliation":[{"name":"Department of Physiology Amsterdam UMC, location VUmc  Amsterdam the Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arezou","family":"Bamyani","sequence":"additional","affiliation":[{"name":"Department of Physiology Amsterdam UMC, location VUmc  Amsterdam the Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gerben\u00a0J.","family":"Schaaf","sequence":"additional","affiliation":[{"name":"Center for Lysosomal and Metabolic Diseases Erasmus University Medical Center  Rotterdam the Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Albertus","family":"Beishuizen","sequence":"additional","affiliation":[{"name":"Intensive care Center Medisch Spectrum Twente  Enschede the Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chris","family":"Dickhoff","sequence":"additional","affiliation":[{"name":"Department of Surgery Amsterdam UMC, location VUmc  Amsterdam the Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Reinier\u00a0A.","family":"Boon","sequence":"additional","affiliation":[{"name":"Department of Physiology Amsterdam UMC, location VUmc  Amsterdam the Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Leo","family":"Heunks","sequence":"additional","affiliation":[{"name":"Department of Intensive Care Medicine Radboudumc  Nijmegen the Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tyler\u00a0J.","family":"Kirby","sequence":"additional","affiliation":[{"name":"Department of Physiology Amsterdam UMC, location VUmc  Amsterdam the Netherlands"},{"name":"Division of Cardiovascular Medicine, Department of Internal Medicine University of Kentucky  Lexington Kentucky USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8808-4813","authenticated-orcid":false,"given":"Coen\u00a0A.\u00a0C.","family":"Ottenheijm","sequence":"additional","affiliation":[{"name":"Department of Physiology Amsterdam UMC, location VUmc  Amsterdam the Netherlands"},{"name":"Department of Cellular and Molecular Medicine University of Arizona  Tucson Arizona 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of Cachexia, Sarcopenia and 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