Ruxolitinib: A new hope for ventilator‐induced diaphragm dysfunction

• DOI: 10.1111/apha.14128
• Publication Date: 2024-03-29T09:14:33Z
• Authors: Alex B. Addinsall; Nicola Cacciani; Noah Moruzzi; Hazem Akkad; Alice Maestri; Per‐Olof Berggren; Anna Widgren; Jonas Bergquist; Tamara Tchkonia; James L. Kirkland; Lars Larsson
• Keywords: Male; 0303 health sciences; VIDD; Diaphragm; myosin; Physiology and Anatomy; Respiration, Artificial; Rats; critical care; mitochondria; STAT3; Rats, Sprague-Dawley; 03 medical and health sciences; Pyrimidines; post-translational modification; diaphragm; Nitriles; Animals; Pyrazoles; Fysiologi och anatomi

AbstractAimMechanical ventilation (MV) results in diminished diaphragm size and strength, termed ventilator‐induced diaphragm dysfunction (VIDD). 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.MethodsRats were subjected to 5 days 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.ResultsCMV significantly reduced diaphragm size and specific force by 45% (p < 0.01), associated with a two‐fold P‐STAT3 upregulation (p < 0.001). CMV disrupted mitochondrial content and reduced the oxygen consumption rate (p < 0.01). Expression of the motor protein myosin was unaffected, however CMV alters myosin function via post‐translational modifications (PTMs). Daily administration of JI increased animal survival (40% vs. 87%; p < 0.05), restricted P‐STAT3 (p < 0.001), and preserved diaphragm size and specific force. JI was associated with preserved mitochondrial content and respiratory function (p < 0.01), and the reversal or augmentation of myosin deamidation PTMs of the rod and head region.ConclusionJI 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‐induced PTMs of myosin. These results demonstrate the potential of repurposing Ruxolitinib for treatment of VIDD.