Global Knockout of AMP-Activated Protein Kinase Alpha Subunits Attenuates the Hypoxic Ventilatory Response in Mice
The AMP-activated protein kinase (AMPK) is a heterotrimer composed of catalytic and regulatory β subunits. AMPK monitors the AMP:ATP ratio as an index of metabolic stress and, when activated, adjusts cell metabolism to maintain ATP supply. Previously we have proposed that AMPK may also underpin hypoxia-response coupling in the carotid bodies, which mediate the entire ventilatory response of the body to acute hypoxia. We therefore sought to determine whether or not AMPK was sufficient and necessary for this process by global knockout of the catalytic alpha subunits in mice.
AMPK1 and AMPK2 knockout mice (European Mutant Mouse Archive) were bred onto a C57BL/6: 129/X1 background to obtain knockout (–/–) animals. Breathing during normoxia (21% O2) and the hypoxic ventilatory response to 8% O2 (3 min) were monitored using a Respiromax plethysmography system (Columbus Instruments). Minute ventilation at rest was lower in AMPK1–/– (1.7 ± 0.1 ml/g/min) and AMPK2–/– (1.6 ± 0.1 ml/g/min) mice when compared to controls (2.3 ± 0.1 ml/g/min, P < 0.0004). Most significantly, the increase in minute ventilation triggered by hypoxia was attenuated in AMPK2–/– mice (3.8 ± 2.8%) when compared with controls (19.0 ± 4.1%, P < 0.005). These data provide further support for the new hypothesis that AMPK regulates oxygen and thereby energy supply at the whole body level.
Funded by the American Heart Association and the Wellcome Trust.
Wyatt, C. N.,
Jordan, H. L.,
Barr, B. L.,
Hardie, D. G.,
& Evans, A. M.
(2010). Global Knockout of AMP-Activated Protein Kinase Alpha Subunits Attenuates the Hypoxic Ventilatory Response in Mice. The FASEB Journal, 24 (Meeting Abstract Supplement).