AMPK deficiency blocks the hypoxic ventilatory response and thus precipitates hypoventilation and apnea

RATIONALE: Modulation of breathing by hypoxia accommodates variations in oxygen demand and supply during, for example, sleep and ascent to altitude, yet the precise molecular mechanisms remain controversial. Among those genes influenced by natural selection in high-altitude populations is that for the AMP-activated protein kinase (AMPK) α1 catalytic subunit, which governs cell autonomous adaptations during metabolic stress.

OBJECTIVE: We investigated whether or not AMPK-α1 and/or AMPK-α2 are required for the hypoxic ventilatory response and the mechanism of ventilatory dysfunctions arising from AMPK deficiency.

METHODS: Experiments utilized plethysmography, electrophysiology, functional magnetic resonance imaging and immediate early gene (cfos) 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 comprise the hypoxia-responsive respiratory network from carotid body to brainstem.

MEASUREMENTS AND MAIN RESULTS: AMPK-α1+α2 deletion virtually abolished the hypoxic ventilatory response, and ventilatory depression during hypoxia was exacerbated under anesthesia. Rather than hyperventilating, mice lacking AMPK-α1+α2 exhibited hypoventilation and apnea during hypoxia, the primary precipitant being loss of AMPK-α1 expression. However, the carotid bodies of AMPK knockouts remained exquisitely sensitive to hypoxia, contrary to the view that the hypoxic ventilatory response is solely determined by increased carotid body afferent input to the brainstem. Regardless, functional magnetic resonance imaging and cfos expression revealed reduced activation by hypoxia of well-defined dorsal and ventral brainstem nuclei.

CONCLUSIONS: AMPK is required to coordinate the activation by hypoxia of brainstem respiratory networks and deficiencies in AMPK expression precipitate hypoventilation and apnea, even where carotid body afferent input is normal.