Abstract 20435: Metabolomic Profiling of Adenylate Kinase AK1-/- and AK2+/- Transgenic Mice: Effect of Physical Stress
Introduction: Cytosolic and mitochondrial intermembrane adenylate kinase isoforms, AK1 and AK2, comprise an integrated metabolic monitoring system facilitating mitochondrial ATP export and delivery to cellular ATPases. Hearts with AK1 deficiency have compromised metabolic response to stress while AK2 transgenic mice have not been studied yet.
Hypothesis: Here we tested hypothesis that stress metabolomic profiling of AK1 and AK2 genetic deficiencies will reveal alterations and biomarkers of compromised intracellular energetic communication and metabolic signaling.
Methods: We have employed HPLC, GC/MS and 18O-assisted 31P NMR techniques to obtain metabolomic profile of plasma and heart extracts of AK1−/− and AK2+/− transgenic mice.
Results: We generated AK2+/− transgenic mice while homozygous AK2−/− deficiency was embryonically lethal. Metabolic profiling revealed that WT and AK1−/− mice although have different basal plasma metabolic phenotype it diverge much more after treadmill exercise (Figure). Similarly AK2+/− mice have different plasma metabolic profile at baseline and separates further from WT after treadmill exercise (Figure). Among most significant plasma metabolites critical in the discrimination between AK1 and WT were β-hydroxybutyrate and amino acids such as tryptophan and lysine. AK1−/− mice hearts had lower βATP and βADP and higher G6P 18O-labeling rates as well as higher levels of G6P, Fr1,6P and Pi. Among most significant plasma metabolites critical in the discrimination between WT and AK2+/− phenotype were adenosine, tyrosine, tryptophan and hypoxanthine. In AK2+/−hearts ATP depletion and AMPK activation during ischemia was greater compared to WT.
Conclusion: Adenylate kinase AK2 isoform is vital for cell energetics and metabolic signaling and its deficiency causes embryonic lethality. Stress metabolic profiling reveals more significant differences in metabolic phenotype between WT and AK1−/− and AK2+/− transgenic mice.
- © 2010 by American Heart Association, Inc.