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.; Cacciani, Nicola; Moruzzi, Noah; Akkad, Hazem; Maestri, Alice; Berggren, Per Olof; Widegren, Anna; Bergquist, Jonas; Tchkonia, Tamara; Kirkland, James L.; Larsson, Lars.
In: Acta Physiologica, Vol. 240, No. 5, e14128, 2024.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Ruxolitinib
T2 - A new hope for ventilator-induced diaphragm dysfunction
AU - Addinsall, Alex B.
AU - Cacciani, Nicola
AU - Moruzzi, Noah
AU - Akkad, Hazem
AU - Maestri, Alice
AU - Berggren, Per Olof
AU - Widegren, Anna
AU - Bergquist, Jonas
AU - Tchkonia, Tamara
AU - Kirkland, James L.
AU - Larsson, Lars
N1 - Publisher Copyright: © 2024 The Authors. Acta Physiologica published by John Wiley & Sons Ltd on behalf of Scandinavian Physiological Society.
PY - 2024
Y1 - 2024
N2 - 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.
AB - 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.
KW - critical care
KW - diaphragm
KW - mitochondria
KW - myosin
KW - post-translational modification
KW - STAT3
KW - VIDD
U2 - 10.1111/apha.14128
DO - 10.1111/apha.14128
M3 - Journal article
C2 - 38551103
AN - SCOPUS:85189560763
VL - 240
JO - Acta Physiologica
JF - Acta Physiologica
SN - 1748-1708
IS - 5
M1 - e14128
ER -
ID: 390190287