Abstract
AimsAdenylate 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 ResultsCardiac-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.ConclusionModest 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.
Highlights
Adenylate kinase (AK) is a key enzyme in energy homeostasis involved in the synthesis, equilibration and regulation of adenine nucleotides (Dzeja et al, 2007b)
Transgenic AK1 mRNA was absent from were harvested (WT) mice and profoundly expressed in both AK1 heterozygotes (WT/AK1) and homozygotes (AK1/AK1) (P = 0.0014 and P < 0.0001, respectively) (Supplementary Figure 2A)
Total AK1 mRNA was elevated in the WT/AK1 and AK1/AK1 compared to WT/WT (P = 0.0179 and P < 0.0001, respectively) (Supplementary Figure 2B)
Summary
Adenylate kinase (AK) is a key enzyme in energy homeostasis involved in the synthesis, equilibration and regulation of adenine nucleotides (Dzeja et al, 2007b). AK1 catalyses the reversible reaction 2ADP ↔ ATP + AMP (Dzeja et al, 1998, 1999) thereby allowing interchange of a phosphoryl group between adenine nucleotides (i.e., AMP, ADP, and ATP, the sum of which is termed total adenine nucleotides or TAN pool) (Dzeja et al, 1985) This complements the creatine kinase (CK) system by providing a secondary mechanism for intracellular phosphotransfer. The AMP generated acts as a metabolic signal to activate adenosine monophosphate-activated protein kinase (AMPK), which is a master regulator, promoting energy production and reducing energy consumption via multiple signalling cascades (Frederich and Balschi, 2002; Dzeja et al, 2007b) In this way, AK can be said to monitor cellular metabolic state, generating signal via AMP when energy supply is limited, thereby promoting a return to energy homeostasis (Dzeja and Terzic, 2009)
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