AMPK 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. Key to this are two reflex responses, hypoxic pulmonary vasoconstriction (HPV), which aids ventilation-perfusion matching at the lungs, and the hypoxic ventilatory response (HVR) which accelerates ventilation. In 2004 I proposed that HPV might be mediated by the AMP-activated protein kinase, which governs cell autonomous metabolic homeostasis. Pharmacological evidence was presented in support of this view, and the hypothesis extended to incorporate a role for AMPK in regulating carotid body afferent input responses during hypoxia and thus the HVR. The present article reviews our subsequent findings on these matters and those of others, which provide strong support for the view that AMPK mediates HPV. AMPK is also critical to the HVR, but against our expectations it is not required for carotid body activation during hypoxia. Contrary to current consensus in this respect, our findings suggest that AMPK deficiency blocks the HVR at the level of the brainstem, even when afferent input responses from the carotid body are normal. We have therefore revised our hypothesis on the HVR, now proposing 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. Nevertheless, in general outcomes are consistent with the original hypothesis, that the role of AMPK has evolved, through natural selection, to extend to the regulation of breathing, and thus oxygen and energy (ATP) supply to the whole body.

AMPK and the Need to Breathe and Feed: What’s the Matter with Oxygen?

“…Notably, A2 neurons provide afferent inputs to and determine, together with the carotid body, activation by hypoxia of A1/C1 neurons within the RVLM [119] and the rCPG [1,120], the position of which aligns well with the ventral active region identified by fMRI analysis [107]. Through these projections of the NTS, AMPK could thus support HVR [10,112] by either direct or indirect modulation of the rCPG [1,120], and perhaps by also aiding the coordination of functional hyperaemia [121]. Carotid body afferent discharge of AMPK knockout mice remains exquisitely sensitive to falls in PO 2 , and ventilatory responses to hypercapnia remain unaffected even during severe hypoxia.…”

“…It is becoming evident that AMPK also phosphorylates and thus modulates a variety of targets that fall outside of its originally proposed role in the maintenance of metabolic homeostasis [10,11,[66][67][68]. For example, AMPK not only phosphorylates and thus inactivates the pore-forming α subunits of multiple Ca 2+ -activated potassium channels (K Ca 1.1 and K Ca 3.1) [45,69], the voltage-gated potassium channel K V 1.5 [37][38][39] and the ATP-inhibited K ATP channel (Kir6.2) [70], but also phosphorylates and activates the α subunit of the voltage-gated potassium channel Kv2.1 [46].…”

“…It seems plausible that within these specialised NTS neurons, AMPK could very effectively integrate decreased ATP supply due to local hypoxia with increased ATP usage consequent to afferent inputs from peripheral chemoreceptors. The firing frequency of action potentials within these NTS neurons could thus be modulated by AMPK in a manner proportional to the overall ATP demand in the receiving, activated neurons [10,112]. Neuronal energy supply and activity across the entire circuit, from NTS to rCPG, may in turn be supported by direct activation during hypoxia of lactate and/or ATP release from astrocytes throughout the NTS, RVLM and rCPG [114,[123][124][125], to which AMPK may also contribute by balancing neuronal TCA cycle dynamics [126].…”

“…The mechanisms of hypoxia-response coupling in those specialised cells that coordinate cardiorespiratory reflex responses to falls in oxygen availability remain keenly debated topics, nowhere more so than with respect to HVR and HPV. However, emerging evidence now strongly suggests that the AMP-activated protein kinase (AMPK) might facilitate both HVR and HPV [10]. This hypothesis [11,12] was built on prior observations that mitochondria of oxygen-sensing cells were exquisitely sensitive to hypoxia, and the proposal that this was due to the selective expression in these cells of a form of cytochrome C oxidase (COX) that was uniquely sensitive to changing PO 2 within the physiological range [13,14].…”

Anti-fatigue Effects of Ginseng Antler Yam Tang Modulation of Oxidative Stress Signaling in a Mice Model

“…Therefore, the antioxidant system protects against exercise-induced oxidative damage, and reduced physical fatigue and hypoxias [13][14] by controlling the body's oxidative stress response. 5'-ampk-activated protein kinase (AMPK) regulates the role of the body in the incoming and input response of the carotid artery during hypoxia, thereby regulating the hypoxia and oxygenation response [15] . AMPK provides oxygen and ATP to the whole body through the regulation of respiration.…”