Proceedings of The Physiological Society

Physiology 2016 (Dublin, Ireland) (2016) Proc Physiol Soc 37, PCA007

Poster Communications

Is AMPK required for acute acclimation to hypoxia?

S. Hartmann1, A. M. Evans1

1. Centre for Integrative Physiology, University of Edinburgh, Edinburgh, United Kingdom.


During hypoxia ventilatory adjustments are critical to the maintenance of oxygen (O2) delivery during sleep or ascent to altitude (1). We have recently demonstrated that the AMP-activated protein kinase (AMPK), a ubiquitously expressed metabolic sensor (2), is required for the hypoxic ventilatory response (HVR). Briefly, in mice with targeted deletion of the catalytic AMPK-α1 and -α2 subunits in tyrosine hydroxylase (TH)-expressing cells, including the O2-sensing carotid body type I cells and catecholaminergic neurons of the brainstem, the HVR was attenuated and apnoea-duration index augmented during hypoxia (3). Here we report on further investigations into the impact of AMPK deletion on the HVR. AMPK-α1+α2 double knockout (AMPK dKO, n=6) and control (AMPK-α1+α2 floxed, n=8) animals were placed in an unrestrained whole body plethysmography chamber, and changes in breathing frequency (breaths/min), tidal volume (ml/g) and minute ventilation (Mv, ml/min/g) monitored during exposure to mild (12% O2) or severe (8% O2) hypoxia for 10min; all results are reported as mean±SEM. At 8% O2, control mice exhibited acute increases in Mv (21.2±9% after 1min, relative to normoxic breathing (21% O2)) followed by respiratory depression that returned Mv to normoxic levels (4±9% at 5min; -4.8±5.5% at 10min), as reported previously (4). By contrast, throughout the period of hypoxia AMPK dKO mice exhibited severe and persistent hypoventilation (Mv = -8.6±6% at 1min, -33.3±6% at 5min; -29±4.5% at 10min) relative to normoxia. A ventilatory deficit in AMPK dKO mice was also observed upon exposure to mild hypoxia (control versus (vs) knockout: 42.8±8% vs 16.5±6.7% at 1min, 21.6±9.7% vs -1.4±8.4% at 5min; 20.3±11.3% vs -4.4±7.7% at 10min). During 8% O2 apnoeas (complete cessations of ventilatory effort >0.6 sec) of controls displayed a clear time-dependent reduction of frequency (min-1: 3.4±0.7 at 2-3min; 1.4±0.4 at 5-6min; 0.6±0.1 at 8-9min), which was absent or markedly attenuated in AMPK dKO mice (4±0.7 at 2-3min; 3.5±0.7 at 5-6min; 2.9±0.7 at 8-9min). This time-dependent reduction in apnoea frequency was not observed for control or knockout mice upon exposure to mild hypoxia (12% O2), where apnoea frequency was comparable between controls and knockout mice (min-1: 0.8±0.3 vs 1±0.3 at 2-3min; 0.5±0.2 vs 1.2±0.4 at 5-6min; 1±0.4 vs 0.8±0.3 at 8-9min). Most intriguingly, these measures of apnoea frequency are equivalent in magnitude to that which control mice exhibited after 10min acute acclimation to severe hypoxia (8% O2). We conclude that upon exposure to severe, but not mild, hypoxia mice engage a compensatory mechanism that reduces apnoea frequency in a manner dependent on AMPK expression. This adds further weight to our proposal (3) that modulators of AMPK activity or expression could ameliorate sleep disordered breathing associated with metabolic syndrome-related disorders or ascent to altitude.

Where applicable, experiments conform with Society ethical requirements