PT  - JOURNAL ARTICLE
AU  - Amira D. Mahmoud
AU  - Andrew P. Holmes
AU  - Sandy MacMillan
AU  - Oluseye A. Ogunbayo
AU  - Christopher N. Wyatt
AU  - Mark L. Dallas
AU  - Prem Kumar
AU  - Marc Foretz
AU  - Benoit Viollet
AU  - A. Mark Evans
TI  - The hypoxic ventilatory response is facilitated by the activation of Lkb1-AMPK signalling pathways downstream of the carotid bodies
AID  - 10.1101/604900
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 604900
4099  - http://biorxiv.org/content/early/2019/04/10/604900.short
4100  - http://biorxiv.org/content/early/2019/04/10/604900.full
AB  - We recently demonstrated that the role of the AMP-activated protein kinase (AMPK), a ubiquitously expressed enzyme that governs cell-autonomous metabolic homeostasis, has been extended to system-level control of breathing and thus oxygen and energy (ATP) supply to the body. Here we assess the contribution to the hypoxic ventilatory response (HVR) of two upstream kinases that govern the activities of AMPK. Lkb1, which activates AMPK in response to metabolic stress and CaMKK2 which mediates the alternative Ca2+-dependent mechanism of AMPK activation. HVRs remained unaffected in mice with global deletion of the CaMKK2 gene. By contrast, HVRs were markedly attenuated in mice with conditional deletion of LKB1 in catecholaminergic cells, including carotid body type I cells and brainstem respiratory networks. In these mice hypoxia evoked hypoventilation, apnoea and Cheyne-Stokes-like breathing, rather than hyperventilation. Attenuation of HVRs, albeit less severe, was also conferred in mice carrying ∼90% knockdown of Lkb1 expression. Carotid body afferent input responses were retained following either ∼90% knockdown of Lkb1 or AMPK deletion. In marked contrast, LKB1 deletion virtually abolished carotid body afferent discharge during normoxia, hypoxia and hypercapnia. We conclude that Lkb1 and AMPK, but not CaMKK2, facilitate HVRs at a site downstream of the carotid bodies.