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 hypothesized 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. More significantly still, AMPK deficiency led to marked hypoventilation, rather than hyperventilation, and frequent prolonged apneas during hypoxia. Deficits in AMPK expression or activity may therefore compromise system responses to hypoxia or other metabolic stressors and precipitate, sleep-disordered breathing and hypertension, which are associated with either ascent to altitude and metabolic syndrome-related disorders.
The present project will utilize confocal imaging, electrophysiology, functional and resting-state MRI to explore further the neuronal circuits via which AMPK deficiency precipitates respiratory dysfunction associated with the metabolic syndrome.
Evans AM, Mahmoud AD, Moral-Sanz J, Hartmann S. (2016). The emerging role of AMPK in the regulation of breathing and oxygen supply. Biochem J, 473, 2561–2572. See also Editorial by O'Halloran, K. D. (2016). A paradigm shift in oxygen sensing with a twist in the tale! Biochem. J., 473, 2687-2689.
Mahmoud, A.D., Lewis, S., Juricic, L., Udoh, U.A., Hartmann, S., Jansen, M.A., Ogunbayo, O.A., Puggioni, P., Holmes, A.P., Kumar, P., Navarro-Dorado, J., Foretz, M., Viollet, B., Dutia, M.B., Marshall, I., Evans, A.M. (2016). AMP-activated Protein Kinase Deficiency Blocks the Hypoxic Ventilatory Response and Thus Precipitates Hypoventilation and Apnea. AJRCCM, 193, 1032-1043.
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