{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T00:41:05Z","timestamp":1792629665321,"version":"4.5.0"},"reference-count":59,"publisher":"Oxford University Press (OUP)","issue":"10","license":[{"start":{"date-parts":[[2015,5,1]],"date-time":"2015-05-01T00:00:00Z","timestamp":1430438400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2015,5,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Rationale<\/jats:title>\n                    <jats:p>The clinical significance of diaphragm weakness in critically ill patients is evident: it prolongs ventilator dependency, and increases morbidity and duration of hospital stay. To date, the nature of diaphragm weakness and its underlying pathophysiologic mechanisms are poorly understood.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>We hypothesized that diaphragm muscle fibers of mechanically ventilated critically ill patients display atrophy and contractile weakness, and that the ubiquitin\u2013proteasome pathway is activated in the diaphragm.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We obtained diaphragm muscle biopsies from 22 critically ill patients who received mechanical ventilation before surgery and compared these with biopsies obtained from patients during thoracic surgery for resection of a suspected early lung malignancy (control subjects). In a proof-of-concept study in a muscle-specific ring finger protein-1 (MuRF-1) knockout mouse model, we evaluated the role of the ubiquitin\u2013proteasome pathway in the development of contractile weakness during mechanical ventilation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Measurements and Main Results<\/jats:title>\n                    <jats:p>Both slow- and fast-twitch diaphragm muscle fibers of critically ill patients had approximately 25% smaller cross-sectional area, and had contractile force reduced by half or more. Markers of the ubiquitin\u2013proteasome pathway were significantly up-regulated in the diaphragm of critically ill patients. Finally, MuRF-1 knockout mice were protected against the development of diaphragm contractile weakness during mechanical ventilation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>These findings show that diaphragm muscle fibers of critically ill patients display atrophy and severe contractile weakness, and in the diaphragm of critically ill patients the ubiquitin\u2013proteasome pathway is activated. This study provides rationale for the development of treatment strategies that target the contractility of diaphragm fibers to facilitate weaning.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1164\/rccm.201412-2214oc","type":"journal-article","created":{"date-parts":[[2015,3,11]],"date-time":"2015-03-11T15:27:34Z","timestamp":1426087654000},"page":"1126-1138","source":"Crossref","is-referenced-by-count":200,"title":["Diaphragm Muscle Fiber Weakness and Ubiquitin\u2013Proteasome Activation in Critically Ill Patients"],"prefix":"10.1093","volume":"191","author":[{"given":"Pleuni E.","family":"Hooijman","sequence":"first","affiliation":[{"name":"Department of Physiology"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Albertus","family":"Beishuizen","sequence":"additional","affiliation":[{"name":"Department of Intensive Care"},{"name":"Intensive Care and Medisch Spectrum Twente, Enschede, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian C.","family":"Witt","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Operative Intensive Care and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monique C.","family":"de Waard","sequence":"additional","affiliation":[{"name":"Department of Intensive Care"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Armand R. 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