Abstract 10723: Chronic Creatine-deficiency is not the Underlying Cause of Cardiac Dysfunction in Mice Lacking the Creatine Biosynthetic Enzyme Arginine:glycine Amidinotransferase
Background: Arginine:glycine amidinotransferase catalyses the first step in creatine biosynthesis, such that AGAT knockout (KO) mice fed a creatine-free diet have whole body creatine-deficiency. Unlike existing models of creatine-deficiency this approach avoids accumulation of potentially confounding guanidino pre-cursors. We hypothesised that AGAT-KO mice would exhibit cardiac dysfunction rescuable by dietary creatine supplementation, thereby implying causality.
Methods & Results: Absence of myocardial phosphocreatine was confirmed by 31P-MRS, with no change in ATP levels. LV pressures were measured in vivo via a 1F Millar mikro-tip catheter with 1% isoflurane. Creatine-free KO mice had a pronounced hemodynamic phenotype of low LV systolic pressure and heart rate, with impaired contractility (dP/dtmax), relaxation (dP/dtmin) and inotropic reserve compared to wild-type. Contrary to expectations, dietary supplementation with 0.5% creatine for 7 days or 7 weeks corrected LV systolic pressure but no other hemodynamic parameter, despite myocardial creatine returning to normal. KO mice had low plasma homoarginine (HA) levels (WT 0.21±0.01 vs KO 0.03±0.02 μmol/L, p=0.001) implicating a hitherto unknown role for AGAT protein in HA biosynthesis. Crucially, supplementation with HA (14mg/L in drinking water for 10 days) completely rescued all other hemodynamic parameters, indicating that low HA rather than creatine loss is the main driver of cardiac dysfunction. AGAT-KO mice had low heart weights that normalised rapidly with creatine-feeding coincident with increased body water, which may reflect the role of creatine as osmolyte. Conclusions: AGAT-KO mice exhibit chronotropic, inotropic and lusitropic deficits in vivo that are independent of myocardial creatine levels. This supports the view that chronic creatine-deficiency per se is not sufficient to cause cardiac dysfunction in otherwise normal hearts.
- © 2013 by American Heart Association, Inc.