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VID increases dependence, prolongs weaning, and increases discharge mortality rates. The Janus kinase (JAK)\/Signal Transducer and Activator of Transcription (STAT) pathway is implicated in VIDD, upregulated following MV. JAK\/STAT inhibition alleviates chronic muscle wasting conditions. This study aimed to explore the therapeutic potential of Ruxolitinib, an FDA approved JAK1\/2 inhibitor (JI) for the treatment of VIDD.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Rats were subjected to 5\u2009days controlled MV (CMV) with and without daily Ruxolitinib gavage. Muscle fiber size and function were assessed. RNAseq, mitochondrial morphology, respirometry, and mass spectrometry were determined.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>CMV significantly reduced diaphragm size and specific force by 45% (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.01), associated with a two\u2010fold P\u2010STAT3 upregulation (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.001). CMV disrupted mitochondrial content and reduced the oxygen consumption rate (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.01). Expression of the motor protein myosin was unaffected, however CMV alters myosin function via post\u2010translational modifications (PTMs). Daily administration of JI increased animal survival (40% vs. 87%; <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05), restricted P\u2010STAT3 (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.001), and preserved diaphragm size and specific force. JI was associated with preserved mitochondrial content and respiratory function (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.01), and the reversal or augmentation of myosin deamidation PTMs of the rod and head region.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>JI preserved diaphragm function, leading to increased survival in an experimental model of VIDD. Functional enhancement was associated with maintenance of mitochondrial content and respiration and the reversal of ventilator\u2010induced PTMs of myosin. These results demonstrate the potential of repurposing Ruxolitinib for treatment of VIDD.<\/jats:p><\/jats:sec>","DOI":"10.1111\/apha.14128","type":"journal-article","created":{"date-parts":[[2024,3,29]],"date-time":"2024-03-29T09:14:33Z","timestamp":1711703673000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Ruxolitinib: A new hope for ventilator\u2010induced diaphragm dysfunction"],"prefix":"10.1111","volume":"240","author":[{"given":"Alex B.","family":"Addinsall","sequence":"first","affiliation":[{"name":"Basic and Clinical Muscle Biology, Department of Physiology and Pharmacology Karolinska Institute  Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicola","family":"Cacciani","sequence":"additional","affiliation":[{"name":"Basic and Clinical Muscle Biology, Department of Physiology and Pharmacology Karolinska Institute  Stockholm Sweden"},{"name":"Center for Molecular 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