Ruxolitinib: A new hope for ventilator-induced diaphragm dysfunction

Research output: Contribution to journalJournal articleResearchpeer-review

Documents

  • Fulltext

    Final published version, 8.16 MB, PDF document

  • Addinsall, Alex Bernard
  • Nicola Cacciani
  • Noah Moruzzi
  • Hazem Akkad
  • Alice Maestri
  • Per Olof Berggren
  • Anna Widegren
  • Jonas Bergquist
  • Tamara Tchkonia
  • James L. Kirkland
  • Lars Larsson

Aim: Mechanical 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. Methods: Rats 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. Results: CMV 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. Conclusion: 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-induced PTMs of myosin. These results demonstrate the potential of repurposing Ruxolitinib for treatment of VIDD.

Original languageEnglish
Article numbere14128
JournalActa Physiologica
Volume240
Issue number5
Number of pages14
ISSN1748-1708
DOIs
Publication statusPublished - 2024
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2024 The Authors. Acta Physiologica published by John Wiley & Sons Ltd on behalf of Scandinavian Physiological Society.

    Research areas

  • critical care, diaphragm, mitochondria, myosin, post-translational modification, STAT3, VIDD

ID: 390190287