Haikel Dridi1,2, Boris Jung1,3, Mohamad Yehya1, Aurelien Daurat4,5, Steven Reiken2, Johan Moreau1, Andrew R Marks2, Stefan Matecki1,5, Alain Lacampagne1, Samir Jaber1,4. 1. PhyMedExp, Montpellier University, INSERM, CNRS, Montpellier, France. 2. Department of Physiology and Cellular Biophysics, Clyde and Helen Wu Center for Molecular Cardiology Columbia University College of Physicians and Surgeons, New York, NY. 3. Medical Intensive Care Unit, Montpellier University and Montpellier University Health Care Center, Montpellier, France. 4. Saint Eloi Department of Anesthesiology and Critical Care Medicine, Montpellier University and Montpellier University Health Care Center, Montpellier, France. 5. Arnaud de Villeneuve Physiological Department, Montpellier University and Montpellier University Health Care Center, Montpellier, France.
Abstract
OBJECTIVES: Mechanical ventilation is associated with primary diaphragmatic dysfunction, also termed ventilator-induced diaphragmatic dysfunction. Studies evaluating diaphragmatic function recovery after extubation are lacking. We evaluated early and late recoveries from ventilator-induced diaphragmatic dysfunction in a mouse model. DESIGN: Experimental randomized study. SETTING: Research laboratory. SUBJECTS: C57/BL6 mice. INTERVENTIONS: Six groups of C57/BL6 mice. Mice were ventilated for 6 hours and then euthanatized immediately (n = 18), or 1 (n = 18) or 10 days after extubation with (n = 5) and without S107 (n = 16) treatment. Mice euthanatized immediately after 6 hours of anesthesia (n = 15) or after 6 hours of anesthesia and 10 days of recovery (n = 5) served as controls. MEASUREMENTS AND MAIN RESULTS: For each group, diaphragm force production, posttranslational modification of ryanodine receptor, oxidative stress, proteolysis, and cross-sectional areas were evaluated. After 6 hours of mechanical ventilation, diaphragm force production was decreased by 25-30%, restored to the control levels 1 day after extubation, and secondarily decreased by 20% 10 days after extubation compared with controls. Ryanodine receptor was protein kinase A-hyperphosphorylated, S-nitrosylated, oxidized, and depleted of its stabilizing subunit calstabin-1 6 hours after the onset of the mechanical ventilation, 1 and 10 days after extubation. Post extubation treatment with S107, a Rycal drug that stabilizes the ryanodine complex, did reverse the loss of diaphragmatic force associated with mechanical ventilation. Total protein oxidation was restored to the control levels 1 day after extubation. Markers of proteolysis including calpain 1 and calpain 2 remained activated 10 days after extubation without significant changes in cross-sectional areas. CONCLUSIONS: We report that mechanical ventilation is associated with a late diaphragmatic dysfunction related to a structural alteration of the ryanodine complex that is reversed with the S107 treatment.
OBJECTIVES: Mechanical ventilation is associated with primary diaphragmatic dysfunction, also termed ventilator-induced diaphragmatic dysfunction. Studies evaluating diaphragmatic function recovery after extubation are lacking. We evaluated early and late recoveries from ventilator-induced diaphragmatic dysfunction in a mouse model. DESIGN: Experimental randomized study. SETTING: Research laboratory. SUBJECTS: C57/BL6 mice. INTERVENTIONS: Six groups of C57/BL6 mice. Mice were ventilated for 6 hours and then euthanatized immediately (n = 18), or 1 (n = 18) or 10 days after extubation with (n = 5) and without S107 (n = 16) treatment. Mice euthanatized immediately after 6 hours of anesthesia (n = 15) or after 6 hours of anesthesia and 10 days of recovery (n = 5) served as controls. MEASUREMENTS AND MAIN RESULTS: For each group, diaphragm force production, posttranslational modification of ryanodine receptor, oxidative stress, proteolysis, and cross-sectional areas were evaluated. After 6 hours of mechanical ventilation, diaphragm force production was decreased by 25-30%, restored to the control levels 1 day after extubation, and secondarily decreased by 20% 10 days after extubation compared with controls. Ryanodine receptor was protein kinase A-hyperphosphorylated, S-nitrosylated, oxidized, and depleted of its stabilizing subunit calstabin-1 6 hours after the onset of the mechanical ventilation, 1 and 10 days after extubation. Post extubation treatment with S107, a Rycal drug that stabilizes the ryanodine complex, did reverse the loss of diaphragmatic force associated with mechanical ventilation. Total protein oxidation was restored to the control levels 1 day after extubation. Markers of proteolysis including calpain 1 and calpain 2 remained activated 10 days after extubation without significant changes in cross-sectional areas. CONCLUSIONS: We report that mechanical ventilation is associated with a late diaphragmatic dysfunction related to a structural alteration of the ryanodine complex that is reversed with the S107 treatment.
Authors: Haikel Dridi; Wei Wu; Steven R Reiken; Rachel M Ofer; Yang Liu; Qi Yuan; Leah Sittenfeld; Jared Kushner; Antoine Muchir; Howard J Worman; Andrew R Marks Journal: Hum Mol Genet Date: 2021-02-25 Impact factor: 6.150