title: Respiratory muscle contractile inactivity induced by mechanical ventilation in piglets leads to leaky ryanodine receptors and diaphragm weakness.
abstract: Respiratory muscle contractile inactivity during mechanical ventilation (MV) induces diaphragm muscle weakness, a condition referred to as ventilator-induced diaphragmatic dysfunction (VIDD). Although VIDD pathophysiological mechanisms are still not fully understood, it has been recently suggested that remodeling of the sarcoplasmic reticulum (SR) calcium release channel/ryanodine receptors (RyR1) in the diaphragm is a proximal mechanism of VIDD. Here, we used piglets, a large animal model of VIDD that is more relevant to human pathophysiology, to determine whether RyR1 alterations are observed in the presence of diaphragm weakness. In piglets, diaphragm weakness induced by 72 h of respiratory muscle unloading was associated with SR RyR1 remodeling and abnormal resting SR Ca2+leak in the diaphragm. Specifically, following controlled mechanical ventilation, diaphragm contractile function was reduced. Moreover, RyR1 macromolecular complexes were more oxidized, S-nitrosylated and phosphorylated at Ser-2844 and depleted of the stabilizing subunit calstabin1 compared with controls on adaptive support ventilation that maintains diaphragmatic contractile activity. Our study strongly supports the hypothesis that RyR1 is a potential therapeutic target in VIDD and the interest of using small molecule drugs to prevent RyR1-mediated SR Ca2+leak induced by respiratory muscle unloading in patients who require controlled mechanical ventilation.
authors.affiliation: Inserm U1046, CNRS UMR 91214, Université de Montpellier, Centre Hospitalier Regional Universitaire de Montpellier, 34295, Montpellier, France. Stephan.Matecki@umontp.fr.
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.|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: Inserm U1046, CNRS UMR 91214, Université de Montpellier, Centre Hospitalier Regional Universitaire de Montpellier, 34295, Montpellier, France.
authors.forename: Valerie
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.|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: Inserm U1046, CNRS UMR 91214, Université de Montpellier, Centre Hospitalier Regional Universitaire de Montpellier, 34295, Montpellier, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Lacampagne
mesh_terms: D000818:Animals; D003964:Diaphragm / Q000378:metabolism / Q000503:physiopathology*; D005260:Female; D023421:Models, Animal; D018908:Muscle Weakness / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D012121:Respiration, Artificial; D012132:Respiratory Muscles / Q000378:metabolism / Q000503:physiopathology*; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism*; D013552:Swine; D012122:Ventilators, Mechanical
chemical_list: D019837:Ryanodine Receptor Calcium Release Channel
keywords: Calcium channel; Calcium homeostasis; Diaphragm; Mechanical ventilation