The emerging role of AMPK in the regulation of breathing and oxygen supply

Abstract

Regulation of breathing is critical to our capacity to accommodate deficits in oxygen availability and demand during, for example, sleep and ascent to altitude. It is generally accepted that a fall in arterial oxygen increases afferent discharge from the carotid bodies to the brainstem and thus delivers increased ventilatory drive, which restores oxygen supply and protects against hypoventilation and apnoea. However, the precise molecular mechanisms involved remain unclear. We recently identified as critical to this process the AMP-activated protein kinase (AMPK), which is key to the cell-autonomous regulation of metabolic homoeostasis. This observation is significant for many reasons, not least because recent studies suggest that the gene for the AMPK-α1 catalytic subunit has been subjected to natural selection in high-altitude populations. It would appear, therefore, that evolutionary pressures have led to AMPK being utilized to regulate oxygen delivery and thus energy supply to the body in the short, medium and longer term. Contrary to current consensus, however, our findings suggest that AMPK regulates ventilation at the level of the caudal brainstem, even when afferent input responses from the carotid body are normal. We therefore hypothesize that AMPK integrates local hypoxic stress at defined loci within the brainstem respiratory network with an index of peripheral hypoxic status, namely afferent chemosensory inputs. Allied to this, AMPK is critical to the control of hypoxic pulmonary vasoconstriction and thus ventilation–perfusion matching at the lungs and may also determine oxygen supply to the foetus by, for example, modulating utero-placental blood flow.

AMPK breathing and oxygen supply

“…While the aforementioned findings run counter to the view that increased afferent discharge from carotid body to brainstem alone determines the ventilatory response to a fall in arterial PO2, they do provide substantial support for an alternative yet inclusive perspective, namely that the HVR is determined by the coordinated action of the carotid body and an hypoxia-responsive circuit within the brainstem (Curran et al, 2000;Evans et al, 2016;Gourine and Funk, 2017;Mahmoud et al, 2015b;Smith et al, 1993;Teppema and Dahan, 2010). To date little emphasis has been placed on the role of hypoxia-sensing at the level of the brainstem, perhaps because the HVR is so effectively abolished by resection of the carotid sinus nerve in humans (Wade et al, 1970).…”

Flaxseed Polysaccharide Altering Colonic Gene Expression of Lipid Metabolism and Energy Metabolism in Obese Rat

“…Both NDUFA4L2 and COX4I2 can reduce the capacity for mitochondrial oxygen consumption and act to limit mitochondrial ROS production during hypoxia, by reducing the activity of complex I and cytochrome c oxidase respectively [51]. Researchers found the deterioration of respiratory capacity due to differences at the level of respiratory chain complexes in obese individuals, among which, particularly, electron transport at the level of complexes I and IV was most affected [52]. Therefore, FP intervention upregulated Ndufa4l2…”

Acute oxygen sensing by the carotid body: a rattlebag of molecular mechanisms

“…Eventually, using a careful and complex knockout strategy, Dr Evans's laboratory successfully deleted both catalytic subunits of AMPK in tissue containing tyrosine hydroxylase (critically including the carotid body). Then, using unrestrained plethysmography techniques and electrophysiology, they and their collaborators demonstrated that this knockout did indeed alter the acute hypoxic ventilatory response but that it was not via an effect on the oxygen sensing ability of the carotid body (Evans et al 2016;Mahmoud et al 2016).…”

“…Then, using unrestrained plethysmography techniques and electrophysiology, they and their collaborators demonstrated that this knockout did indeed alter the acute hypoxic ventilatory response but that it was not via an effect on the oxygen sensing ability of the carotid body (Evans et al . ; Mahmoud et al . ).…”