Ruxolitinib: A new hope for ventilator-induced diaphragm dysfunction

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Ruxolitinib : A new hope for ventilator-induced diaphragm dysfunction

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.

Cacciani, Nicola (author): Karolinska Inst, Dept Physiol & Pharmacol, Basic & Clin Muscle Biol, Stockholm, Sweden.;Karolinska Inst, Ctr Mol Med, Stockholm, Sweden.

Moruzzi, Noah (author): Karolinska Institutet,Karolinska Inst, Rolf Luft Res Ctr Diabet & Endocrinol, Dept Mol Med & Surg, Stockholm, Sweden.

Akkad, Hazem (author): Karolinska Inst, Dept Physiol & Pharmacol, Basic & Clin Muscle Biol, Stockholm, Sweden.

Maestri, Alice (author): Karolinska Institutet,Karolinska Inst, Ctr Mol Med, Stockholm, Sweden.;Karolinska Inst, Dept Med, Div Cardiovasc Med, Solna, Sweden.

Berggren, Per-Olof (author): Karolinska Institutet,Karolinska Inst, Rolf Luft Res Ctr Diabet & Endocrinol, Dept Mol Med & Surg, Stockholm, Sweden.

Widgren, Anna (author): Uppsala universitet,Analytisk kemi

Bergquist, Jonas (author): Uppsala universitet,Analytisk kemi

Tchkonia, Tamara (author): Viron Mol Med Inst, Muscle Biol Program, Boston, MA USA.

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.

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.
In: Acta Physiologica. - : John Wiley & Sons. - 1748-1708 .- 1748-1716. ; 240:5

Related links:: https://doi.org/10.1...; show more...; https://uu.diva-port... (primary) (Raw object); https://urn.kb.se/re...; https://doi.org/10.1...; http://kipublication...; show less...

Journal article (peer-reviewed)

Abstract Subject headings

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

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ref (subject category)
art (subject category)

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By the author/editor: Addinsall, Alex ...; Cacciani, Nicola; Moruzzi, Noah; Akkad, Hazem; Maestri, Alice; Berggren, Per-Ol ...; show more...; Widgren, Anna; Bergquist, Jonas; Tchkonia, Tamara; Kirkland, James ...; Larsson, Lars; show less...

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MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Basic Medicine; and Physiology

Articles in the publication: Acta Physiologic ...

By the university: Uppsala University; Karolinska Institutet

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