Living without creatine: Unchanged exercise capacity and response to chronic myocardial infarction in creatine-deficient mice

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,...

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Main Authors: Lygate, C, Aksentijevic, D, Dawson, D, Ten Hove, M, Phillips, D, De Bono, J, Medway, D, Sebag-Montefiore, L, Hunyor, I, Channon, K, Clarke, K, Zervou, S, Watkins, H, Balaban, R, Neubauer, S
格式: Journal article
语言:English
出版: 2013
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author Lygate, C
Aksentijevic, D
Dawson, D
Ten Hove, M
Phillips, D
De Bono, J
Medway, D
Sebag-Montefiore, L
Hunyor, I
Channon, K
Clarke, K
Zervou, S
Watkins, H
Balaban, R
Neubauer, S
author_facet Lygate, C
Aksentijevic, D
Dawson, D
Ten Hove, M
Phillips, D
De Bono, J
Medway, D
Sebag-Montefiore, L
Hunyor, I
Channon, K
Clarke, K
Zervou, S
Watkins, H
Balaban, R
Neubauer, S
author_sort Lygate, C
collection OXFORD
description 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. © 2013 American Heart Association, Inc.
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spelling oxford-uuid:07bda1f7-74db-494f-86f8-aaba25928f172022-03-26T09:09:12ZLiving without creatine: Unchanged exercise capacity and response to chronic myocardial infarction in creatine-deficient miceJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:07bda1f7-74db-494f-86f8-aaba25928f17EnglishSymplectic Elements at Oxford2013Lygate, CAksentijevic, DDawson, DTen Hove, MPhillips, DDe Bono, JMedway, DSebag-Montefiore, LHunyor, IChannon, KClarke, KZervou, SWatkins, HBalaban, RNeubauer, SRATIONALE:: 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. © 2013 American Heart Association, Inc.
spellingShingle Lygate, C
Aksentijevic, D
Dawson, D
Ten Hove, M
Phillips, D
De Bono, J
Medway, D
Sebag-Montefiore, L
Hunyor, I
Channon, K
Clarke, K
Zervou, S
Watkins, H
Balaban, R
Neubauer, S
Living without creatine: Unchanged exercise capacity and response to chronic myocardial infarction in creatine-deficient mice
title Living without creatine: Unchanged exercise capacity and response to chronic myocardial infarction in creatine-deficient mice
title_full Living without creatine: Unchanged exercise capacity and response to chronic myocardial infarction in creatine-deficient mice
title_fullStr Living without creatine: Unchanged exercise capacity and response to chronic myocardial infarction in creatine-deficient mice
title_full_unstemmed Living without creatine: Unchanged exercise capacity and response to chronic myocardial infarction in creatine-deficient mice
title_short Living without creatine: Unchanged exercise capacity and response to chronic myocardial infarction in creatine-deficient mice
title_sort living without creatine unchanged exercise capacity and response to chronic myocardial infarction in creatine deficient mice
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