AMP-activated Protein Kinase Deficiency Blocks the Hypoxic Ventilatory Response and Thus Precipitates Hypoventilation and Apnea

• DOI: 10.1164/rccm.201508-1667oc
• Publication Date: 2015-12-16T00:26:03Z
• Authors: Amira D. Mahmoud; Sophronia Lewis; Lara Juričić; Utibe-Abasi Udoh; Sandy Hartmann; Maurits A. Jansen; Oluseye A. Ogunbayo; Paolo Puggioni; Andrew P. Holmes; Prem Kumar; Jorge Navarro-Dorado; Marc Foretz; Benoit Viollet; Mayank B. Dutia; Ian Marshall; A. Mark Evans
• Keywords: Hypoxia; Hypoxic ventilatory response; AMP-Activated Protein Kinase

Modulation of breathing by hypoxia accommodates variations in oxygen demand and supply during, for example, sleep ascent to altitude, but the precise molecular mechanisms this phenomenon remain controversial. Among genes influenced natural selection high-altitude populations is one 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 hypoxic ventilatory response mechanism dysfunctions arising from AMPK deficiency.We used plethysmography, electrophysiology, functional magnetic resonance imaging, immediate early gene (c-fos) expression assess mice with conditional deletion catecholaminergic cells, compose hypoxia-responsive respiratory network carotid body brainstem.AMPK-α1 virtually abolished response, depression was exacerbated under anesthesia. Rather than hyperventilating, lacking exhibited hypoventilation apnea hypoxia, primary precipitant being loss expression. However, bodies AMPK-knockout remained exquisitely sensitive contrary view that determined solely increased afferent input brainstem. Regardless, imaging c-fos revealed reduced activation well-defined dorsal ventral brainstem nuclei.AMPK coordinate networks, deficiencies precipitate apnea, even when normal.