title: Mechanical ventilation triggers abnormal mitochondrial dynamics and morphology in the diaphragm.
abstract: The diaphragm is a unique skeletal muscle designed to be rhythmically active throughout life, such that its sustained inactivation by the medical intervention of mechanical ventilation (MV) represents an unanticipated physiological state in evolutionary terms. Within a short period after initiating MV, the diaphragm develops muscle atrophy, damage, and diminished strength, and many of these features appear to arise from mitochondrial dysfunction. Notably, in response to metabolic perturbations, mitochondria fuse, divide, and interact with neighboring organelles to remodel their shape and functional properties-a process collectively known as mitochondrial dynamics. Using a quantitative electron microscopy approach, here we show that diaphragm contractile inactivity induced by 6 h of MV in mice leads to fragmentation of intermyofibrillar (IMF) but not subsarcolemmal (SS) mitochondria. Furthermore, physical interactions between adjacent organellar membranes were less abundant in IMF mitochondria during MV. The profusion proteins Mfn2 and OPA1 were unchanged, whereas abundance and activation status of the profission protein Drp1 were increased in the diaphragm following MV. Overall, our results suggest that mitochondrial morphological abnormalities characterized by excessive fission-fragmentation represent early events during MV, which could potentially contribute to the rapid onset of mitochondrial dysfunction, maladaptive signaling, and associated contractile dysfunction of the diaphragm.
authors.affiliation: Center for Mitochondrial and Epigenomic Medicine, The Children's Hospital of Philadelphia and University of Pennsylvania, Philadelphia, Pennsylvania;
authors.forename: Martin
authors.initials: M
authors.lastname: Picard
authors.affiliation: Meakins-Christie Laboratories, McGill University Health Centre Research Institute, Montreal, Quebec, Canada; Critical Care and Respiratory Divisions, McGill University Health Centre, Montreal, Quebec, Canada;
authors.forename: Ilan
authors.initials: I
authors.lastname: Azuelos
authors.affiliation: Meakins-Christie Laboratories, McGill University Health Centre Research Institute, Montreal, Quebec, Canada; Department of Critical Care Medicine and Anesthesiology, Saint Eloi Teaching Hospital, and Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale (INSERM U-1046), Montpellier University, Montpellier, France;
authors.forename: Boris
authors.initials: B
authors.lastname: Jung
authors.affiliation: Meakins-Christie Laboratories, McGill University Health Centre Research Institute, Montreal, Quebec, Canada;
authors.forename: Christian
authors.initials: C
authors.lastname: Giordano
authors.affiliation: Department of Critical Care Medicine and Anesthesiology, Saint Eloi Teaching Hospital, and Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale (INSERM U-1046), Montpellier University, Montpellier, France;
authors.forename: Stefan
authors.initials: S
authors.lastname: Matecki
authors.affiliation: Meakins-Christie Laboratories, McGill University Health Centre Research Institute, Montreal, Quebec, Canada; Critical Care and Respiratory Divisions, McGill University Health Centre, Montreal, Quebec, Canada;
authors.forename: Sabah
authors.initials: S
authors.lastname: Hussain
authors.affiliation: EM Research Services, Newcastle University, Newcastle upon Tyne, United Kingdom;
authors.forename: Kathryn
authors.initials: K
authors.lastname: White
authors.affiliation: Meakins-Christie Laboratories, McGill University Health Centre Research Institute, Montreal, Quebec, Canada;
authors.forename: Tong
authors.initials: T
authors.lastname: Li
authors.affiliation: Meakins-Christie Laboratories, McGill University Health Centre Research Institute, Montreal, Quebec, Canada;
authors.forename: Feng
authors.initials: F
authors.lastname: Liang
authors.affiliation: Department of Medicine and Department of Epidemiology, Biostatistics & Occupational Health, McGill University, Montreal, Quebec, Canada;
authors.forename: Andrea
authors.initials: A
authors.lastname: Benedetti
authors.affiliation: Department of Neurology/Neurosurgery and Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada; and.
authors.forename: Benoit J
authors.initials: BJ
authors.lastname: Gentil
authors.affiliation: Faculty of Pharmacy, Université de Montréal, Montreal, Quebec, Canada.
authors.forename: Yan
authors.initials: Y
authors.lastname: Burelle
authors.affiliation: Meakins-Christie Laboratories, McGill University Health Centre Research Institute, Montreal, Quebec, Canada; Critical Care and Respiratory Divisions, McGill University Health Centre, Montreal, Quebec, Canada; basil.petrof@mcgill.ca.
authors.forename: Basil J
authors.initials: BJ
authors.lastname: Petrof
mesh_terms: D000818:Animals; D003964:Diaphragm / Q000378:metabolism / Q000502:physiology*; D034281:Dynamins / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism / Q000502:physiology*; D008931:Mitochondria, Muscle / Q000378:metabolism / Q000502:physiology; D063154:Mitochondrial Dynamics / Q000502:physiology*; D009119:Muscle Contraction / Q000502:physiology; D018482:Muscle, Skeletal / Q000378:metabolism / Q000502:physiology; D009133:Muscular Atrophy / Q000378:metabolism / Q000503:physiopathology; D012121:Respiration, Artificial / Q000379:methods
chemical_list: C486391:Dnm1l protein, mouse; D034281:Dynamins
keywords: electron microscopy; intermyofibrillar mitochondria; mitochondrial dynamics; mitochondrial fragmentation; subsarcolemmal mitochondria; ventilator-induced diaphragmatic dysfunction