title: AMP-activated Protein Kinase Deficiency Blocks the Hypoxic Ventilatory Response and Thus Precipitates Hypoventilation and Apnea.
abstract: Modulation of breathing by hypoxia accommodates variations in oxygen demand and supply during, for example, sleep and ascent to altitude, but the precise molecular mechanisms of this phenomenon remain controversial. Among the genes influenced by natural selection in high-altitude populations is one for the adenosine monophosphate-activated protein kinase (AMPK) α1-catalytic subunit, which governs cell-autonomous adaptations during metabolic stress.
  
  
  
  We investigated whether AMPK-α1 and/or AMPK-α2 are required for the hypoxic ventilatory response and the mechanism of ventilatory dysfunctions arising from AMPK deficiency.
  
  
  
  We used plethysmography, electrophysiology, functional magnetic resonance imaging, and immediate early gene (c-fos) expression to assess the hypoxic ventilatory response of mice with conditional deletion of the AMPK-α1 and/or AMPK-α2 genes in catecholaminergic cells, which compose the hypoxia-responsive respiratory network from carotid body to brainstem.
  
  
  
  AMPK-α1 and AMPK-α2 deletion virtually abolished the hypoxic ventilatory response, and ventilatory depression during hypoxia was exacerbated under anesthesia. Rather than hyperventilating, mice lacking AMPK-α1 and AMPK-α2 exhibited hypoventilation and apnea during hypoxia, with the primary precipitant being loss of AMPK-α1 expression. However, the carotid bodies of AMPK-knockout mice remained exquisitely sensitive to hypoxia, contrary to the view that the hypoxic ventilatory response is determined solely by increased carotid body afferent input to the brainstem. Regardless, functional magnetic resonance imaging and c-fos expression revealed reduced activation by hypoxia of well-defined dorsal and ventral brainstem nuclei.
  
  
  
  AMPK is required to coordinate the activation by hypoxia of brainstem respiratory networks, and deficiencies in AMPK expression precipitate hypoventilation and apnea, even when carotid body afferent input is normal.
authors.affiliation: 1 Centre for Integrative Physiology.
authors.forename: Amira D
authors.initials: AD
authors.lastname: Mahmoud
authors.affiliation: 1 Centre for Integrative Physiology.
authors.forename: Sophronia
authors.initials: S
authors.lastname: Lewis
authors.affiliation: 2 Centre for Cardiovascular Science, and.
authors.forename: Lara
authors.initials: L
authors.lastname: Juričić
authors.affiliation: 1 Centre for Integrative Physiology.
authors.forename: Utibe-Abasi
authors.initials: UA
authors.lastname: Udoh
authors.affiliation: 1 Centre for Integrative Physiology.
authors.forename: Sandy
authors.initials: S
authors.lastname: Hartmann
authors.affiliation: 2 Centre for Cardiovascular Science, and.
authors.forename: Maurits A
authors.initials: MA
authors.lastname: Jansen
authors.affiliation: 1 Centre for Integrative Physiology.
authors.forename: Oluseye A
authors.initials: OA
authors.lastname: Ogunbayo
authors.affiliation: 1 Centre for Integrative Physiology.
authors.forename: Paolo
authors.initials: P
authors.lastname: Puggioni
authors.affiliation: 3 Institute of Clinical Sciences, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Holmes
authors.affiliation: 3 Institute of Clinical Sciences, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Prem
authors.initials: P
authors.lastname: Kumar
authors.affiliation: 1 Centre for Integrative Physiology.
authors.forename: Jorge
authors.initials: J
authors.lastname: Navarro-Dorado
authors.affiliation: 4 Institut Cochin, INSERM U1016, Paris, France.|5 CNRS UMR8104, Paris, France; and.|6 Université Paris Descartes, Paris, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Foretz
authors.affiliation: 4 Institut Cochin, INSERM U1016, Paris, France.|5 CNRS UMR8104, Paris, France; and.|6 Université Paris Descartes, Paris, France.
authors.forename: Benoit
authors.initials: B
authors.lastname: Viollet
authors.affiliation: 1 Centre for Integrative Physiology.
authors.forename: Mayank B
authors.initials: MB
authors.lastname: Dutia
authors.affiliation: 7 Centre for Clinical Brain Sciences, College of Medicine and Veterinary Medicine, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Ian
authors.initials: I
authors.lastname: Marshall
authors.affiliation: 1 Centre for Integrative Physiology.
authors.forename: A Mark
authors.identifier: 0000-0002-4650-7208
authors.initials: AM
authors.lastname: Evans
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000172:deficiency*; D000818:Animals; D001049:Apnea / Q000503:physiopathology*; D004195:Disease Models, Animal; D004594:Electrophysiology; D007040:Hypoventilation / Q000503:physiopathology*; D000860:Hypoxia / Q000503:physiopathology*; D008279:Magnetic Resonance Imaging; D051379:Mice; D018345:Mice, Knockout; D010991:Plethysmography
chemical_list: D055372:AMP-Activated Protein Kinases
keywords: adenosine monophosphate–activated protein kinase; apnea; brainstem; hypoxia; ventilation