Impaired cardiac contractile function in AGAT knockout mice devoid of creatine is rescued by homoarginine but not creatine.
Faller KME., Atzler D., McAndrew DJ., Zervou S., Whittington HJ., Simon JN., Aksentijevic D., Hove MT., Choe C-U., Isbrandt D., Casadei B., Schneider JE., Neubauer S., Lygate CA.
Creatine buffers cellular ATP via the creatine kinase reaction. Creatine levels are reduced in heart failure, but their contribution to pathophysiology is unclear. Arginine:glycine amidinotransferase (AGAT) in the kidney catalyses both the first step in creatine biosynthesis as well as homoarginine synthesis. AGAT-/- mice fed a creatine-free diet have a whole body creatine-deficiency. We hypothesised that AGAT-/- mice would develop cardiac dysfunction and rescue by dietary creatine would imply causality.Withdrawal of dietary creatine in AGAT-/- mice provided an estimate of myocardial creatine efflux of ∼2.7%/day, however, in vivo cardiac function was maintained despite low levels of myocardial creatine. Using AGAT-/- mice naïve to dietary creatine we confirmed absence of phosphocreatine in the heart, but crucially, ATP levels were unchanged. Potential compensatory adaptations were absent, AMPK was not activated and respiration in isolated mitochondria was normal. AGAT-/- mice had rescuable changes in body water and organ weights suggesting a role for creatine as a compatible osmolyte. Creatine-naïve AGAT-/- mice had haemodynamic impairment with low LV systolic pressure and reduced inotropy, lusitropy and contractile reserve. Creatine supplementation only corrected systolic pressure despite normalisation of myocardial creatine. AGAT-/- mice had low plasma homoarginine and supplementation completely rescued all other haemodynamic parameters. Contractile dysfunction in AGAT-/- was confirmed in Langendorff perfused hearts and in creatine-replete isolated cardiomyocytes, indicating that homoarginine is necessary for normal cardiac function.Our findings argue against low myocardial creatine per se as a major contributor to cardiac dysfunction. Conversely, we show that homoarginine deficiency can impair cardiac function, which may explain why low homoarginine is an independent risk factor for multiple cardiovascular diseases.