Abstract 10762: Adaptations to Maintain Energy Homeostasis Compensate for Creatine-Deficiency in GAMT Knockout Mice Following Myocardial Infarction, but May Contribute to Early Mitochondrial Pathology During Aging
Guanidinoacetate N-methyltransferase (GAMT) catalyses the final step of creatine biosynthesis such that GAMT-/- mice have undetectable levels of phosphocreatine (PCr) and creatine, and accumulation of the precursor (phospho-)guanidinoacetate (PGA). We hypothesised that impaired energy transfer would adversely affect remodeling and function post-myocardial infarction (MI), and would be detrimental in the ageing heart. GAMT-/- mice and wildtype controls received MI or sham surgery (n=104), with 3D echocardiography and LV hemodynamics after 6 weeks. Despite GAMT-/- mice having reduced pressure generating capacity at baseline, there was no significant difference in post-MI survival. Infarct size was matched at 40%, and both genotypes exhibited a similar degree of LV dilatation, function, and hypertrophy. To determine whether accumulation of PGA was compensatory, we used 31P-MRS magnetization transfer to measure flux of phosphoryl groups between ATP and guanidinoacetate, but found this to be negligible, strongly suggesting the presence of other compensatory processes. Proteomic analysis failed to identify major protein changes, however activity of the F1F0 ATP synthase in mitochondrial homogenates was 93% higher in GAMT-/- mice at 6 months of age compared to WT (n=6, P<0.01). Activity of key glycolytic enzymes was also quantified: 3-phosphoglycerate kinase was not altered, while glyceraldehyde 3-phosphate dehydrogenase was elevated by 12% (P=0.03) and pyruvate kinase by 36% (P=0.001) in GAMT-/-. Adaptive increases in adenylate kinase activity were not observed. Mitochondrial damage was evident in ageing GAMT-/- mice (>1 year), exhibiting as reduced mitochondrial volume by electron microscopy (KO 42±5% vs WT 50±6%, P<0.001), reduced mtDNA copy number (P=0.004), and lower citrate synthase activity which correlated with age (P<0.05). This mitochondrial pathology was temporally related to further deterioration of in vivo cardiac function and normalisation of F1F0 ATP synthase activity.
Conclusion: adaptive increases in energy production pathways are sufficient to compensate for creatine-deficiency in GAMT-/- mice post-MI and up to one year of age, but long-term creatine deficiency is associated with mitochondrial damage.
- © 2011 by American Heart Association, Inc.