AMPK deficiency blocks the hypoxic ventilatory response and thus precipitates hypoventilation and apnea

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AMPK deficiency blocks the hypoxic ventilatory response and thus precipitates hypoventilation and apnea. / Mahmoud, Amira D; Lewis, Sophronia; Juričić, Lara; Udoh, Utibe-Abasi; Hartmann, Sandy; Jansen, Maurits A; Ogunbayo, Oluseye A; Puggioni, Paolo; Holmes, Andrew P; Kumar, Prem; Navarro-Dorado, Jorge; Foretz, Marc; Viollet, Benoit; Dutia, Mayank B; Marshall, Ian; Evans, A Mark.

In: American Journal of Respiratory and Critical Care Medicine, Vol. 193, No. 9, 01.05.2016.

Research output: Contribution to journalArticlepeer-review

Harvard

Mahmoud, AD, Lewis, S, Juričić, L, Udoh, U-A, Hartmann, S, Jansen, MA, Ogunbayo, OA, Puggioni, P, Holmes, AP, Kumar, P, Navarro-Dorado, J, Foretz, M, Viollet, B, Dutia, MB, Marshall, I & Evans, AM 2016, 'AMPK deficiency blocks the hypoxic ventilatory response and thus precipitates hypoventilation and apnea', American Journal of Respiratory and Critical Care Medicine, vol. 193, no. 9. https://doi.org/10.1164/rccm.201508-1667OC

APA

Mahmoud, A. D., Lewis, S., Juričić, 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). AMPK deficiency blocks the hypoxic ventilatory response and thus precipitates hypoventilation and apnea. American Journal of Respiratory and Critical Care Medicine, 193(9). https://doi.org/10.1164/rccm.201508-1667OC

Vancouver

Author

Mahmoud, Amira D ; Lewis, Sophronia ; Juričić, Lara ; Udoh, Utibe-Abasi ; Hartmann, Sandy ; Jansen, Maurits A ; Ogunbayo, Oluseye A ; Puggioni, Paolo ; Holmes, Andrew P ; Kumar, Prem ; Navarro-Dorado, Jorge ; Foretz, Marc ; Viollet, Benoit ; Dutia, Mayank B ; Marshall, Ian ; Evans, A Mark. / AMPK deficiency blocks the hypoxic ventilatory response and thus precipitates hypoventilation and apnea. In: American Journal of Respiratory and Critical Care Medicine. 2016 ; Vol. 193, No. 9.

Bibtex

@article{9cd2975e9f2444d3a0826058736a4e57,
title = "AMPK deficiency blocks the hypoxic ventilatory response and thus precipitates hypoventilation and apnea",
abstract = "RATIONALE: Modulation of breathing by hypoxia accommodates variations in oxygen demand and supply during, for example, sleep and ascent to altitude, yet the precise molecular mechanisms remain controversial. Among those genes influenced by natural selection in high-altitude populations is that for the AMP-activated protein kinase (AMPK) α1 catalytic subunit, which governs cell autonomous adaptations during metabolic stress.OBJECTIVE: We investigated whether or not AMPK-α1 and/or AMPK-α2 are required for the hypoxic ventilatory response and the mechanism of ventilatory dysfunctions arising from AMPK deficiency.METHODS: Experiments utilized plethysmography, electrophysiology, functional magnetic resonance imaging and immediate early gene (cfos) expression to assess the hypoxic ventilatory response of mice with conditional deletion of the AMPK-α1 and/or AMPK-α2 genes in catecholaminergic cells, which comprise the hypoxia-responsive respiratory network from carotid body to brainstem.MEASUREMENTS AND MAIN RESULTS: AMPK-α1+α2 deletion virtually abolished the hypoxic ventilatory response, and ventilatory depression during hypoxia was exacerbated under anesthesia. Rather than hyperventilating, mice lacking AMPK-α1+α2 exhibited hypoventilation and apnea during hypoxia, the primary precipitant being loss of AMPK-α1 expression. However, the carotid bodies of AMPK knockouts remained exquisitely sensitive to hypoxia, contrary to the view that the hypoxic ventilatory response is solely determined by increased carotid body afferent input to the brainstem. Regardless, functional magnetic resonance imaging and cfos expression revealed reduced activation by hypoxia of well-defined dorsal and ventral brainstem nuclei.CONCLUSIONS: AMPK is required to coordinate the activation by hypoxia of brainstem respiratory networks and deficiencies in AMPK expression precipitate hypoventilation and apnea, even where carotid body afferent input is normal.",
keywords = "AMPK, hypoxia, ventilation, apnoea, brainstem",
author = "Mahmoud, {Amira D} and Sophronia Lewis and Lara Juri{\v c}i{\'c} and Utibe-Abasi Udoh and Sandy Hartmann and Jansen, {Maurits A} and Ogunbayo, {Oluseye A} and Paolo Puggioni and Holmes, {Andrew P} and Prem Kumar and Jorge Navarro-Dorado and Marc Foretz and Benoit Viollet and Dutia, {Mayank B} and Ian Marshall and Evans, {A Mark}",
year = "2016",
month = may,
day = "1",
doi = "10.1164/rccm.201508-1667OC",
language = "English",
volume = "193",
journal = "American Journal of Respiratory and Critical Care Medicine",
issn = "1073-449X",
publisher = "American Thoracic Society",
number = "9",

}

RIS

TY - JOUR

T1 - AMPK deficiency blocks the hypoxic ventilatory response and thus precipitates hypoventilation and apnea

AU - Mahmoud, Amira D

AU - Lewis, Sophronia

AU - Juričić, Lara

AU - Udoh, Utibe-Abasi

AU - Hartmann, Sandy

AU - Jansen, Maurits A

AU - Ogunbayo, Oluseye A

AU - Puggioni, Paolo

AU - Holmes, Andrew P

AU - Kumar, Prem

AU - Navarro-Dorado, Jorge

AU - Foretz, Marc

AU - Viollet, Benoit

AU - Dutia, Mayank B

AU - Marshall, Ian

AU - Evans, A Mark

PY - 2016/5/1

Y1 - 2016/5/1

N2 - RATIONALE: Modulation of breathing by hypoxia accommodates variations in oxygen demand and supply during, for example, sleep and ascent to altitude, yet the precise molecular mechanisms remain controversial. Among those genes influenced by natural selection in high-altitude populations is that for the AMP-activated protein kinase (AMPK) α1 catalytic subunit, which governs cell autonomous adaptations during metabolic stress.OBJECTIVE: We investigated whether or not AMPK-α1 and/or AMPK-α2 are required for the hypoxic ventilatory response and the mechanism of ventilatory dysfunctions arising from AMPK deficiency.METHODS: Experiments utilized plethysmography, electrophysiology, functional magnetic resonance imaging and immediate early gene (cfos) expression to assess the hypoxic ventilatory response of mice with conditional deletion of the AMPK-α1 and/or AMPK-α2 genes in catecholaminergic cells, which comprise the hypoxia-responsive respiratory network from carotid body to brainstem.MEASUREMENTS AND MAIN RESULTS: AMPK-α1+α2 deletion virtually abolished the hypoxic ventilatory response, and ventilatory depression during hypoxia was exacerbated under anesthesia. Rather than hyperventilating, mice lacking AMPK-α1+α2 exhibited hypoventilation and apnea during hypoxia, the primary precipitant being loss of AMPK-α1 expression. However, the carotid bodies of AMPK knockouts remained exquisitely sensitive to hypoxia, contrary to the view that the hypoxic ventilatory response is solely determined by increased carotid body afferent input to the brainstem. Regardless, functional magnetic resonance imaging and cfos expression revealed reduced activation by hypoxia of well-defined dorsal and ventral brainstem nuclei.CONCLUSIONS: AMPK is required to coordinate the activation by hypoxia of brainstem respiratory networks and deficiencies in AMPK expression precipitate hypoventilation and apnea, even where carotid body afferent input is normal.

AB - RATIONALE: Modulation of breathing by hypoxia accommodates variations in oxygen demand and supply during, for example, sleep and ascent to altitude, yet the precise molecular mechanisms remain controversial. Among those genes influenced by natural selection in high-altitude populations is that for the AMP-activated protein kinase (AMPK) α1 catalytic subunit, which governs cell autonomous adaptations during metabolic stress.OBJECTIVE: We investigated whether or not AMPK-α1 and/or AMPK-α2 are required for the hypoxic ventilatory response and the mechanism of ventilatory dysfunctions arising from AMPK deficiency.METHODS: Experiments utilized plethysmography, electrophysiology, functional magnetic resonance imaging and immediate early gene (cfos) expression to assess the hypoxic ventilatory response of mice with conditional deletion of the AMPK-α1 and/or AMPK-α2 genes in catecholaminergic cells, which comprise the hypoxia-responsive respiratory network from carotid body to brainstem.MEASUREMENTS AND MAIN RESULTS: AMPK-α1+α2 deletion virtually abolished the hypoxic ventilatory response, and ventilatory depression during hypoxia was exacerbated under anesthesia. Rather than hyperventilating, mice lacking AMPK-α1+α2 exhibited hypoventilation and apnea during hypoxia, the primary precipitant being loss of AMPK-α1 expression. However, the carotid bodies of AMPK knockouts remained exquisitely sensitive to hypoxia, contrary to the view that the hypoxic ventilatory response is solely determined by increased carotid body afferent input to the brainstem. Regardless, functional magnetic resonance imaging and cfos expression revealed reduced activation by hypoxia of well-defined dorsal and ventral brainstem nuclei.CONCLUSIONS: AMPK is required to coordinate the activation by hypoxia of brainstem respiratory networks and deficiencies in AMPK expression precipitate hypoventilation and apnea, even where carotid body afferent input is normal.

KW - AMPK

KW - hypoxia

KW - ventilation

KW - apnoea

KW - brainstem

U2 - 10.1164/rccm.201508-1667OC

DO - 10.1164/rccm.201508-1667OC

M3 - Article

C2 - 26669206

VL - 193

JO - American Journal of Respiratory and Critical Care Medicine

JF - American Journal of Respiratory and Critical Care Medicine

SN - 1073-449X

IS - 9

ER -