Document Detail

Living without creatine: unchanged exercise capacity and response to chronic myocardial infarction in creatine-deficient mice.
MedLine Citation:
PMID:  23325497     Owner:  NLM     Status:  MEDLINE    
RATIONALE: 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.
METHODS AND 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.
Craig A Lygate; Dunja Aksentijevic; Dana Dawson; Michiel ten Hove; Darci Phillips; Joseph P de Bono; Debra J Medway; Liam Sebag-Montefiore; Imre Hunyor; Keith M Channon; Kieran Clarke; Sevasti Zervou; Hugh Watkins; Robert S Balaban; Stefan Neubauer
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2013-01-16
Journal Detail:
Title:  Circulation research     Volume:  112     ISSN:  1524-4571     ISO Abbreviation:  Circ. Res.     Publication Date:  2013 Mar 
Date Detail:
Created Date:  2013-03-15     Completed Date:  2013-04-24     Revised Date:  2014-10-12    
Medline Journal Info:
Nlm Unique ID:  0047103     Medline TA:  Circ Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  945-55     Citation Subset:  IM    
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MeSH Terms
Adenylate Kinase / metabolism
Creatine / deficiency*
Exercise Tolerance / physiology*
Glycine / analogs & derivatives,  metabolism
Guanidinoacetate N-Methyltransferase / genetics
Heart Failure / etiology,  metabolism,  physiopathology
Mice, Inbred C57BL
Mice, Knockout
Mitochondria, Heart / physiology
Myocardial Infarction / complications,  metabolism,  physiopathology*
Oxygen Consumption / physiology
Physical Conditioning, Animal
Physical Exertion / physiology*
Ventricular Remodeling / physiology
Grant Support
090532//Wellcome Trust; 090532/Z/09/Z//Wellcome Trust; PS/02/002/14893//British Heart Foundation; RG/07/004/22659//British Heart Foundation; RG/10/002/28187//British Heart Foundation
Reg. No./Substance:
EC protein, mouse; EC N-Methyltransferase; EC Kinase; GO52O1A04E/glycocyamine; MU72812GK0/Creatine; TE7660XO1C/Glycine
Comment In:
Circ Res. 2013 Mar 15;112(6):878-80   [PMID:  23493302 ]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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