title: Living without creatine: unchanged exercise capacity and response to chronic myocardial infarction in creatine-deficient mice.
abstract: BACKGROUND
  Creatine is thought to be involved in the spatial and temporal buffering of ATP in energetic organs such as heart and skeletal muscle. Creatine depletion affects force generation during maximal stimulation, while reduced levels of myocardial creatine are a hallmark of the failing heart, leading to the widely held view that creatine is important at high workloads and under conditions of pathological stress.
  
  
  OBJECTIVE
  We therefore hypothesised that the consequences of creatine-deficiency in mice would be impaired running capacity, and exacerbation of heart failure following myocardial infarction.
  
  
  RESULTS
  Surprisingly, mice with whole-body creatine deficiency due to knockout of the biosynthetic enzyme (guanidinoacetate N-methyltransferase [GAMT]) voluntarily ran just as fast and as far as controls (>10 km/night) and performed the same level of work when tested to exhaustion on a treadmill. Furthermore, survival following myocardial infarction was not altered, nor was subsequent left ventricular (LV) remodelling and development of chronic heart failure exacerbated, as measured by 3D-echocardiography and invasive hemodynamics. These findings could not be accounted for by compensatory adaptations, with no differences detected between WT and GAMT(-/-) proteomes. Alternative phosphotransfer mechanisms were explored; adenylate kinase activity was unaltered, and although GAMT(-/-) hearts accumulated the creatine precursor guanidinoacetate, this had negligible energy-transfer activity, while mitochondria retained near normal function.
  
  
  CONCLUSIONS
  Creatine-deficient mice show unaltered maximal exercise capacity and response to chronic myocardial infarction, and no obvious metabolic adaptations. Our results question the paradigm that creatine is essential for high workload and chronic stress responses in heart and skeletal muscle.
authors: Department of Cardiovascular Medicine, Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Oxford, UK. clygate@well.ox.ac.uk
authors: Craig A
authors: CA
authors: Lygate
authors: Dunja
authors: D
authors: Aksentijevic
authors: Dana
authors: D
authors: Dawson
authors: Michiel
authors: M
authors: ten Hove
authors: Darci
authors: D
authors: Phillips
authors: Joseph P
authors: JP
authors: de Bono
authors: Debra J
authors: DJ
authors: Medway
authors: Liam
authors: L
authors: Sebag-Montefiore
authors: Imre
authors: I
authors: Hunyor
authors: Keith M
authors: KM
authors: Channon
authors: Kieran
authors: K
authors: Clarke
authors: Sevasti
authors: S
authors: Zervou
authors: Hugh
authors: H
authors: Watkins
authors: Robert S
authors: RS
authors: Balaban
authors: Stefan
authors: S
authors: Neubauer
mesh_terms: D000263:Adenylate Kinase / Q000378:metabolism; D000818:Animals; D003401:Creatine / Q000172:deficiency*; D017079:Exercise Tolerance / Q000502:physiology*; D005260:Female; D005998:Glycine / Q000031:analogs & derivatives / Q000378:metabolism; D050937:Guanidinoacetate N-Methyltransferase / Q000235:genetics; D006333:Heart Failure / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008929:Mitochondria, Heart / Q000502:physiology; D009203:Myocardial Infarction / Q000150:complications / Q000378:metabolism / Q000503:physiopathology*; D010101:Oxygen Consumption / Q000502:physiology; D010805:Physical Conditioning, Animal; D005082:Physical Exertion / Q000502:physiology*; D020257:Ventricular Remodeling / Q000502:physiology
chemical_list: C494507:Gamt protein, mouse; D050937:Guanidinoacetate N-Methyltransferase; D000263:Adenylate Kinase; C004946:glycocyamine; D003401:Creatine; D005998:Glycine