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Subtle Role for Adenylate Kinase 1 in Maintaining Normal Basal Contractile Function and Metabolism in the Murine Heart

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Sevasti Zervou, Debra J. McAndrew, Hannah J. Whittington, Hannah A. Lake, Kyung Chan Park, Kuan Minn Cha, Philip J. Ostrowski, Thomas R. Eykyn, Jürgen E. Schneider, Stefan Neubauer, Craig A. Lygate

Original languageEnglish
Article number623969
JournalFrontiers in Physiology
Volume12
DOIs
Published31 Mar 2021

Bibliographical note

Funding Information: AK1-OE mice were created by the Transgenic Core facility run by Dr. Ben Davies at the Wellcome Centre for Human Genetics, Oxford, United Kingdom. The team helped design the mouse models and performed the blastocyst injection. MRI was performed by Victoria Thornton who sadly died in 2018. Funding. This work was principally supported by British Heart Foundation Programme Grants (RG/13/8/30266 and RG/18/12/34040) to SN and CL. Additional core support was acknowledged from the Oxford BHF Centre for Research Excellence and Wellcome Trust Core Award (Grant No. 203141/Z/16/Z). TE acknowledges support from the NIHR Biomedical Research Centre at Guy?s and St Thomas? NHS Foundation Trust and KCL; the Centre of Excellence in Medical Engineering funded by the Wellcome Trust and Engineering and EPSRC (WT 203148/Z/16/Z); the BHF Centre of Research Excellence (RE/18/2/34213); and the KCL Comprehensive Cancer Imaging Centre funded by the Cancer Research United Kingdom and EPSRC in association with the MRC and the Department of Health (DoH). Publisher Copyright: © Copyright © 2021 Zervou, McAndrew, Whittington, Lake, Park, Cha, Ostrowski, Eykyn, Schneider, Neubauer and Lygate. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

King's Authors

Abstract

Aims: Adenylate kinase 1 (AK1) catalyses the reaction 2ADP ↔ ATP + AMP, extracting extra energy under metabolic stress and promoting energetic homeostasis. We hypothesised that increased AK1 activity would have negligible effects at rest, but protect against ischaemia/reperfusion (I/R) injury. Methods and Results: Cardiac-specific AK1 overexpressing mice (AK1-OE) had 31% higher AK1 activity (P = 0.009), with unchanged total creatine kinase and citrate synthase activities. Male AK1-OE exhibited mild in vivo dysfunction at baseline with lower LV pressure, impaired relaxation, and contractile reserve. LV weight was 19% higher in AK1-OE males due to higher tissue water content in the absence of hypertrophy or fibrosis. AK1-OE hearts had significantly raised creatine, unaltered total adenine nucleotides, and 20% higher AMP levels (P = 0.05), but AMP-activated protein kinase was not activated (P = 0.85). 1H-NMR revealed significant differences in LV metabolite levels compared to wild-type, with aspartate, tyrosine, sphingomyelin, cholesterol all elevated, whereas taurine and triglycerides were significantly lower. Ex vivo global no-flow I/R, caused four-of-seven AK1-OE hearts to develop terminal arrhythmia (cf. zero WT), yet surviving AK1-OE hearts had improved functional recovery. However, AK1-OE did not influence infarct size in vivo and arrhythmias were only observed ex vivo, probably as an artefact of adenine nucleotide loss during cannulation. Conclusion: Modest elevation of AK1 may improve functional recovery following I/R, but has unexpected impact on LV weight, function and metabolite levels under basal resting conditions, suggesting a more nuanced role for AK1 underpinning myocardial energy homeostasis and not just as a response to stress.

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