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Ruxolitinib :
Ruxolitinib : A new hope for ventilator-induced diaphragm dysfunction
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- Addinsall, Alex B. (author)
- Karolinska Inst, Dept Physiol & Pharmacol, Basic & Clin Muscle Biol, Stockholm, Sweden.;Univ Copenhagen, Novo Nord Fdn Ctr Basic Metab Res, Copenhagen, Denmark.
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- Cacciani, Nicola (author)
- Karolinska Inst, Dept Physiol & Pharmacol, Basic & Clin Muscle Biol, Stockholm, Sweden.;Karolinska Inst, Ctr Mol Med, Stockholm, Sweden.
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- Moruzzi, Noah (author)
- Karolinska Institutet,Karolinska Inst, Rolf Luft Res Ctr Diabet & Endocrinol, Dept Mol Med & Surg, Stockholm, Sweden.
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- Akkad, Hazem (author)
- Karolinska Inst, Dept Physiol & Pharmacol, Basic & Clin Muscle Biol, Stockholm, Sweden.
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- Maestri, Alice (author)
- Karolinska Institutet,Karolinska Inst, Ctr Mol Med, Stockholm, Sweden.;Karolinska Inst, Dept Med, Div Cardiovasc Med, Solna, Sweden.
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- Berggren, Per-Olof (author)
- Karolinska Institutet,Karolinska Inst, Rolf Luft Res Ctr Diabet & Endocrinol, Dept Mol Med & Surg, Stockholm, Sweden.
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- Widgren, Anna (author)
- Uppsala universitet,Analytisk kemi
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- Bergquist, Jonas (author)
- Uppsala universitet,Analytisk kemi
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- Tchkonia, Tamara (author)
- Viron Mol Med Inst, Muscle Biol Program, Boston, MA USA.
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- Kirkland, James L. (author)
- Karolinska Institutet,Mayo Clin, Dept Physiol & Biomed Engn, Rochester, MN USA.;Mayo Clin, Div Gen Internal Med, Rochester, MN USA.,Karolinska Inst, Dept Physiol & Pharmacol, Basic & Clin Muscle Biol, Stockholm, Sweden.;Karolinska Inst, Ctr Mol Med, Stockholm, Sweden.;Viron Mol Med Inst, Muscle Biol Program, Boston, MA USA.;Karolinska Inst, Dept Physiol & Pharmacol, Basic & Clin Muscle Biol Grp, Solnavagen 9, S-17165 Solna, Sweden.
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- Larsson, Lars (author)
- Karolinska Inst, Dept Physiol & Pharmacol, Basic & Clin Muscle Biol, Stockholm, Sweden.;Karolinska Inst, Ctr Mol Med, Stockholm, Sweden.;Viron Mol Med Inst, Muscle Biol Program, Boston, MA USA.;Karolinska Inst, Dept Physiol & Pharmacol, Basic & Clin Muscle Biol Grp, Solnavagen 9, S-17165 Solna, Sweden.
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Karolinska Inst, Dept Physiol & Pharmacol, Basic & Clin Muscle Biol, Stockholm, Sweden;Univ Copenhagen, Novo Nord Fdn Ctr Basic Metab Res, Copenhagen, Denmark. Karolinska Inst, Dept Physiol & Pharmacol, Basic & Clin Muscle Biol, Stockholm, Sweden.;Karolinska Inst, Ctr Mol Med, Stockholm, Sweden. (creator_code:org_t)
- John Wiley & Sons, 2024
- 2024
- English.
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In: Acta Physiologica. - : John Wiley & Sons. - 1748-1708 .- 1748-1716. ; 240:5
- Related links:
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https://uu.diva-port... (primary) (Raw object)
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Abstract
Subject headings
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- 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Fysiologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Physiology (hsv//eng)
Keyword
- critical care
- diaphragm
- mitochondria
- myosin
- post-translational modification
- STAT3
- VIDD
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Addinsall, Alex ...
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Cacciani, Nicola
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Moruzzi, Noah
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Akkad, Hazem
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Maestri, Alice
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Berggren, Per-Ol ...
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show more...
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Widgren, Anna
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Bergquist, Jonas
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Tchkonia, Tamara
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Kirkland, James ...
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Larsson, Lars
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Physiology
- Articles in the publication
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Acta Physiologic ...
- By the university
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Uppsala University
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Karolinska Institutet