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Living without creatine: unchanged exercise capacity and response to chronic myocardial infarction in
Craig A Lygate1, Dunja Aksentijevic, Dana Dawson
1Department of Cardiovascular Medicine, Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Oxford, UK. clygate@well.ox.ac.uk
Insights
Creatine deficiency did not impair running capacity or worsen heart failure in mice. These findings challenge the established view of creatine's essential role in high-demand situations for heart and muscle.
Area of Science:
- Biochemistry
- Physiology
- Cardiology
Background:
- Creatine plays a crucial role in buffering ATP in energy-intensive organs like the heart and skeletal muscle.
- Reduced myocardial creatine levels are observed in heart failure, suggesting importance under stress.
- The prevailing view is that creatine is vital for high workloads and pathological conditions.
Purpose of the Study:
- To investigate the effects of creatine deficiency on running capacity in mice.
- To determine if creatine deficiency exacerbates heart failure following myocardial infarction.
Main Methods:
- Utilized whole-body creatine deficiency in mice by knocking out the guanidinoacetate N-methyltransferase (GAMT) enzyme.
- Assessed running capacity through voluntary running wheels and treadmill exhaustion tests.
- Evaluated heart failure progression using 3D-echocardiography and invasive hemodynamics post-myocardial infarction.
Main Results:
- Creatine-deficient mice exhibited normal running capacity, covering distances over 10 km/night.
- Survival rates and left ventricular remodeling after myocardial infarction were not significantly altered.
- No compensatory proteomic adaptations or significant changes in adenylate kinase activity were observed.
Conclusions:
- Creatine deficiency in mice does not compromise maximal exercise capacity or response to myocardial infarction.
- The study questions the necessity of creatine for high workload and chronic stress in cardiac and skeletal muscle.
- No significant metabolic adaptations were found to explain the unaltered performance 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, 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.
