The Hypoxic Ventilatory Response is Blocked by AMPK Deletion in Catecholaminergic, but not Adrenergic Cells

During hypoxia, ventilatory adjustments are critical to the maintenance of adequate oxygen (O 2 ) delivery, for example during sleep or ascent to altitude (1). We recently demonstrated that the AMP‐activated protein kinase (AMPK), a ubiquitously expressed metabolic sensor (2), protects against hypoventilation and apnea during hypoxia (3). Here, we further investigated the circuit mechanism by which AMPK deficiency impacts the hypoxic ventilatory response (HVR). Using unrestrained whole‐body plethysmography, we compared the effects on the HVR of mice with dual deletion of the AMPK‐α1/α2 catalytic subunits in all catecholaminergic (TH‐positive) cells with the HVR of mice with AMPK‐α1/α2 deletion targeted to adrenergic cells alone (Phenylethanolamine N‐methyltransferase (PNMT)‐positive). Relative to controls (AMPK‐α1/α2 floxed), mice with TH‐Cre driven AMPK deletion (TH AMPK‐α1/α2 dKO) exhibited hypoventilation, characterized by marked attenuation of minute ventilation (p<0.0001) during each minute of exposures to severe hypoxia (8% O 2 ). By contrast, in mice with PNMT‐Cre driven AMPK deletion (PNMT AMPK‐α1/α2 dKO) the HVR was augmented rather than attenuated, although this only reached significance relative to controls (AMPK‐α1/α2 floxed and PNMT Cre) when taken as averages for the whole 10min period of exposure to severe hypoxia (p<0.001–0.0001). As one might expect given these outcomes, the HVR of PNMT AMPK‐α1/α2 dKO mice was significantly greater than that for TH AMPK‐α1/α2 dKO during each full minute of hypoxia (p<0.0001). Furthermore, the apnea‐duration index (ADI) was significantly augmented in TH AMPK‐α1/α2 dKO mice compared to controls (p<0.01–0.0001). By contrast, PNMT AMPK‐α1/α2 dKO mice exhibited a reduction in the average ADI compared to controls (p<0.05–0.01). This reduction in the ADI for PNMT AMPK‐α1/α2 dKO mice was primarily due to a lower number of apneas during the first 3 to 4 minutes of hypoxic exposure, the ADI being comparable to controls between 4 and 10 min. Accordingly, the ADI of PNMT AMPK‐α1/α2 dKO was attenuated at each time point throughout the 10min exposure to hypoxia when compared to TH AMPK‐α1/α2 dKO mice (p<0.0001). In conclusion, we have uncovered a split in the AMPK‐dependent regulation of the catecholaminergic respiratory network during hypoxia, where the HVR is promoted by AMPK‐dependent modulation of noradrenergic inputs, but opposed by AMPK‐dependent modulation of adrenergic inputs. AMPK may thus protect against hypoventilation and apnea through noradrenergic signaling, and might aid restoration of normal CO 2 levels during hypoxic hyperventilation through adrenergic signaling (4). This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .

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