title: Leaky ryanodine receptors contribute to diaphragmatic weakness during mechanical ventilation.
abstract: Ventilator-induced diaphragmatic dysfunction (VIDD) refers to the diaphragm muscle weakness that occurs following prolonged controlled mechanical ventilation (MV). The presence of VIDD impedes recovery from respiratory failure. However, the pathophysiological mechanisms accounting for VIDD are still not fully understood. Here, we show in human subjects and a mouse model of VIDD that MV is associated with rapid remodeling of the sarcoplasmic reticulum (SR) Ca(2+) release channel/ryanodine receptor (RyR1) in the diaphragm. The RyR1 macromolecular complex was oxidized, S-nitrosylated, Ser-2844 phosphorylated, and depleted of the stabilizing subunit calstabin1, following MV. These posttranslational modifications of RyR1 were mediated by both oxidative stress mediated by MV and stimulation of adrenergic signaling resulting from the anesthesia. We demonstrate in the murine model that such abnormal resting SR Ca(2+) leak resulted in reduced contractile function and muscle fiber atrophy for longer duration of MV. Treatment with β-adrenergic antagonists or with S107, a small molecule drug that stabilizes the RyR1-calstabin1 interaction, prevented VIDD. Diaphragmatic dysfunction is common in MV patients and is a major cause of failure to wean patients from ventilator support. This study provides the first evidence to our knowledge of RyR1 alterations as a proximal mechanism underlying VIDD (i.e., loss of function, muscle atrophy) and identifies RyR1 as a potential target for therapeutic intervention.
authors.affiliation: Inserm U1046, CNRS UMR 91214, Université de Montpellier, Centre Hospitalier Regional Universitaire de Montpellier, 34295 Montpellier, France;
authors.forename: Stefan
authors.initials: S
authors.lastname: Matecki
authors.affiliation: Inserm U1046, CNRS UMR 91214, Université de Montpellier, Centre Hospitalier Regional Universitaire de Montpellier, 34295 Montpellier, France;
authors.forename: Haikel
authors.initials: H
authors.lastname: Dridi
authors.affiliation: Inserm U1046, CNRS UMR 91214, Université de Montpellier, Centre Hospitalier Regional Universitaire de Montpellier, 34295 Montpellier, France; Department of Anesthesiology and Critical Care Medicine, St. Eloi Teaching Hospital, 34295 Montpellier, France;
authors.forename: Boris
authors.initials: B
authors.lastname: Jung
authors.affiliation: Inserm U1046, CNRS UMR 91214, Université de Montpellier, Centre Hospitalier Regional Universitaire de Montpellier, 34295 Montpellier, France;
authors.forename: Nathalie
authors.initials: N
authors.lastname: Saint
authors.affiliation: Department of Physiology and Cellular Biophysics, College of Physicians and Surgeons, Columbia University, New York, NY 10032; The Clyde and Helen Wu Center for Molecular Cardiology, College of Physicians and Surgeons, Columbia University, New York, NY 10032; Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY 10032;
authors.forename: Steven R
authors.initials: SR
authors.lastname: Reiken
authors.affiliation: Inserm U1046, CNRS UMR 91214, Université de Montpellier, Centre Hospitalier Regional Universitaire de Montpellier, 34295 Montpellier, France;
authors.forename: Valérie
authors.initials: V
authors.lastname: Scheuermann
authors.affiliation: Inserm U1046, CNRS UMR 91214, Université de Montpellier, Centre Hospitalier Regional Universitaire de Montpellier, 34295 Montpellier, France;
authors.forename: Ségolène
authors.initials: S
authors.lastname: Mrozek
authors.affiliation: Department of Physiology and Cellular Biophysics, College of Physicians and Surgeons, Columbia University, New York, NY 10032; The Clyde and Helen Wu Center for Molecular Cardiology, College of Physicians and Surgeons, Columbia University, New York, NY 10032; Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY 10032;
authors.forename: Gaetano
authors.identifier: 0000-0001-7231-375X
authors.initials: G
authors.lastname: Santulli
authors.affiliation: Department of Physiology and Cellular Biophysics, College of Physicians and Surgeons, Columbia University, New York, NY 10032; The Clyde and Helen Wu Center for Molecular Cardiology, College of Physicians and Surgeons, Columbia University, New York, NY 10032; Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY 10032;
authors.forename: Alisa
authors.initials: A
authors.lastname: Umanskaya
authors.affiliation: Meakins-Christie Laboratories, McGill University and McGill University Hospital Research Institute, Montreal, QC H2X 2P2, Canada.
authors.forename: Basil J
authors.initials: BJ
authors.lastname: Petrof
authors.affiliation: Inserm U1046, CNRS UMR 91214, Université de Montpellier, Centre Hospitalier Regional Universitaire de Montpellier, 34295 Montpellier, France; Department of Anesthesiology and Critical Care Medicine, St. Eloi Teaching Hospital, 34295 Montpellier, France;
authors.forename: Samir
authors.initials: S
authors.lastname: Jaber
authors.affiliation: Department of Physiology and Cellular Biophysics, College of Physicians and Surgeons, Columbia University, New York, NY 10032; The Clyde and Helen Wu Center for Molecular Cardiology, College of Physicians and Surgeons, Columbia University, New York, NY 10032; Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY 10032; arm42@cumc.columbia.edu alain.lacampagne@inserm.fr.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Marks
authors.affiliation: Inserm U1046, CNRS UMR 91214, Université de Montpellier, Centre Hospitalier Regional Universitaire de Montpellier, 34295 Montpellier, France; arm42@cumc.columbia.edu alain.lacampagne@inserm.fr.
authors.forename: Alain
authors.initials: A
authors.lastname: Lacampagne
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D003964:Diaphragm / Q000503:physiopathology*; D006801:Humans; D051379:Mice; D009119:Muscle Contraction; D018384:Oxidative Stress; D011943:Receptors, Adrenergic, beta / Q000502:physiology; D012121:Respiration, Artificial / Q000009:adverse effects*; D019837:Ryanodine Receptor Calcium Release Channel / Q000502:physiology*; D015398:Signal Transduction; D022021:Tacrolimus Binding Proteins / Q000502:physiology; D012122:Ventilators, Mechanical / Q000009:adverse effects
chemical_list: C550432:FKBP1A protein, human; D011943:Receptors, Adrenergic, beta; D019837:Ryanodine Receptor Calcium Release Channel; D022021:Tacrolimus Binding Proteins; D002118:Calcium
keywords: VIDD; beta adrenergic signaling; calcium; excitation–contraction coupling; skeletal muscle