Moderate elevation of intracellular creatine by targeting the creatine transporter protects mice from acute myocardial infarction

Lygate, Craig A.; Bohl, Steffen; Hove, Michiel ten; Faller, Kiterie M E; Ostrowski, Philip J.; Zervou, Sevasti; Medway, Debra J.; Aksentijević, Dunja; Sebag-Montefiore, Liam; Wallis, Julie; Clarke, Kieran; Watkins, Hugh; Schneider, Jürgen; Neubauer, Stefan

doi:10.1093/cvr/cvs272

Cited by 82 publications

(120 citation statements)

References 33 publications

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“…Our results differ significantly from those initially described by Wallis et al where mice with two-to fourfold increases in intracellular Cr concentrations developed cardiac dysfunction spontaneously (21,34,46). Moreover, in these animals, the severity of dysfunction was positively correlated with intracellular Cr concentrations.…”

Section: H376 Specific Elevations In Cardiac Creatine Are Not Toxiccontrasting

confidence: 99%

“…Upon further screening of this transgenic animal model, it was determined that very moderate increases in Cr transport capacity, up to a twofold increase in cardiac Cr content, were well tolerated. More importantly, the authors demonstrated that these increases afforded protection from ischemic insults to the cardiac muscle (21). There are several possible explanations for the discrepancies noted between the transgenic line studied here and those reported in the studies by Wallis and Phillips.…”

Section: H377 Specific Elevations In Cardiac Creatine Are Not Toxiccontrasting

confidence: 46%

“…Moreover, such an increase was clearly demonstrated to be protective in the setting of acute myocardial infarction (21).…”

mentioning

confidence: 96%

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Normal cardiac function in mice with supraphysiological cardiac creatine levels

Santacruz

Hernández

Nienaber

et al. 2014

American Journal of Physiology-Heart and Circulatory Physiology

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DO. Normal cardiac function in mice with supraphysiological cardiac creatine levels. Am J Physiol Heart Circ Physiol 306: H373-H381, 2014. First published November 22, 2013; doi:10.1152/ajpheart.00411.2013.-Creatine and phosphocreatine levels are decreased in heart failure, and reductions in myocellular phosphocreatine levels predict the severity of the disease and portend adverse outcomes. Previous studies of transgenic mouse models with increased creatine content higher than two times baseline showed the development of heart failure and shortened lifespan. Given phosphocreatine's role in buffering ATP content, we tested the hypothesis whether elevated cardiac creatine content would alter cardiac function under normal physiological conditions. Here, we report the creation of transgenic mice that overexpress the human creatine transporter (CrT) in cardiac muscle under the control of the ␣-myosin heavy chain promoter. Cardiac transgene expression was quantified by qRT-PCR, and human CrT protein expression was documented on Western blots and immunohistochemistry using a specific anti-CrT antibody. High-energy phosphate metabolites and cardiac function were measured in transgenic animals and compared with age-matched, wild-type controls. Adult transgenic animals showed increases of 5.7-and 4.7-fold in the content of creatine and free ADP, respectively. Phosphocreatine and ATP levels were two times as high in young transgenic animals but declined to control levels by the time the animals reached 8 wk of age. Transgenic mice appeared to be healthy and had normal life spans. Cardiac morphometry, conscious echocardiography, and pressure-volume loop studies demonstrated mild hypertrophy but normal function. Based on our characterization of the human CrT protein expression, creatine and phosphocreatine content, and cardiac morphometry and function, these transgenic mice provide an in vivo model for examining the therapeutic value of elevated creatine content for cardiac pathologies. cardiac failure; creatine transporter; energy metabolism; phosphocreatins A HALLMARK OF CARDIAC FAILURE is a marked disturbance of energy metabolism. In this condition, the manner in which ATP is buffered and transferred, via the creatine kinase (CK) system, from the mitochondria to utilization sites, is profoundly altered (26). In the early stages of heart failure, myocardial creatine (Cr) and phosphocreatine (PCr) are reduced by as much as 70%, whereas a slow and progressive ATP loss of up to 30 -40% is observed at the latter stages of the disease (4,28,39,45). Moreover, the PCr-to-ATP ratio decreases, and this decrease is a better predictor of overall and cardiovascular-related mortality than traditional indexes such as ejection fraction or New York Heart Association symptomatology (27). These deficits in high-energy metabolites are accompanied by decreases in the activity and expression levels of the CKs in the myocardium (22, 38). Recent reports elegantly illustrated that increased CK function has a protective effect in murine models of ...

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Section: H376 Specific Elevations In Cardiac Creatine Are Not Toxiccontrasting

confidence: 99%

Section: H377 Specific Elevations In Cardiac Creatine Are Not Toxiccontrasting

confidence: 46%

See 1 more Smart Citation

Normal cardiac function in mice with supraphysiological cardiac creatine levels

Santacruz

Hernández

Nienaber

et al. 2014

American Journal of Physiology-Heart and Circulatory Physiology

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“…This was due to an inability to keep the enlarged creatine pool adequately phosphorylated, which adversely affects the energy available from ATP hydrolysis [ 47 ]; and reduced expression of enolase resulting in impaired glycolytic capacity [ 48 ]. However, levels of creatine up to twofold (<140 nmol/mg protein) are well tolerated even in ageing mice [ 49 ], and, using in vivo 1 H-MRS [ 50 ], we therefore pre-selected mice within this range before subjecting them to permanent coronary artery ligation. Six weeks later both WT and CrT-OE groups developed LV remodelling and chronic heart failure, but there was no benefi t associated with maintaining elevated creatine levels throughout.…”

Section: Elevating [Cr] In Heart Failurementioning

confidence: 99%

The Myocardial Creatine Kinase System in the Normal, Ischaemic and Failing Heart

Lygate

Neubauer

2014

Cardiac Energy Metabolism in Health and Disease

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The creatine kinase (CK) system is the fi nal step in cardiac energy metabolism providing a direct link between energy production in the mitochondria and energy utilising ATPases. It acts as an energy storage and transport mechanism and maintains favourable local ATP/ADP ratios, thereby supporting further energy production and high levels of free energy from ATP hydrolysis. Down-regulation of CK activity and myocardial creatine levels is a universal fi nding in chronic heart failure, and the degree of impairment has been shown to be an excellent prognostic indicator in patients. However, it is unclear whether these changes represent epiphenomenon or contribute to disease pathophysiology. This chapter focuses on attempts over the past 20 years to address this question using genetic loss-of-function models in the mouse. Findings from these models have been equivocal and at times contradictory, however, recent evidence suggests that loss of creatine or CK is not detrimental in surgical models of chronic heart failure, providing the clearest evidence to date that such changes do not contribute to dysfunction. Despite this conclusion, over-expression of CK in mouse heart has been found to protect against heart failure and improve survival. In the setting of ischaemia-reperfusion injury, loss of creatine or CK impairs functional recovery and augmentation of either is cardioprotective. We are therefore entering an exciting new era of research in this fi eld aimed at understanding the benefi ts of CK system augmentation and identifying new mechanisms to achieve this without genetic modifi cation for possible future clinical translation.

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“…Recently, it was reported that an increase in cardiac Cr content exerted a protective effect in a rodent model of ischemia and reperfusion (Lygate et al. 2012). Finally, we have demonstrated that Cr supplementation ameliorates oxidative stress caused by doxorubicin in cultured cardiomyocytes (Santacruz et al.…”

Section: Introductionmentioning

confidence: 99%

Hypoxia decreases creatine uptake in cardiomyocytes, while creatine supplementation enhances HIF activation

et al. 2017

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Creatine (Cr), phosphocreatine (PCr), and creatine kinases (CK) comprise an energy shuttle linking ATP production in mitochondria with cellular consumption sites. Myocytes cannot synthesize Cr: these cells depend on uptake across the cell membrane by a specialized creatine transporter (CrT) to maintain intracellular Cr levels. Hypoxia interferes with energy metabolism, including the activity of the creatine energy shuttle, and therefore affects intracellular ATP and PCr levels. Here, we report that exposing cultured cardiomyocytes to low oxygen levels rapidly diminishes Cr transport by decreasing V max and K m. Pharmacological activation of AMP‐activated kinase (AMPK) abrogated the reduction in Cr transport caused by hypoxia. Cr supplementation increases ATP and PCr content in cardiomyocytes subjected to hypoxia, while also significantly augmenting the cellular adaptive response to hypoxia mediated by HIF‐1 activation. Our results indicate that: (1) hypoxia reduces Cr transport in cardiomyocytes in culture, (2) the cytoprotective effects of Cr supplementation are related to enhanced adaptive physiological responses to hypoxia mediated by HIF‐1, and (3) Cr supplementation increases the cellular ATP and PCr content in RNCMs exposed to hypoxia.

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Moderate elevation of intracellular creatine by targeting the creatine transporter protects mice from acute myocardial infarction

Cited by 82 publications

References 33 publications

Normal cardiac function in mice with supraphysiological cardiac creatine levels

Normal cardiac function in mice with supraphysiological cardiac creatine levels

The Myocardial Creatine Kinase System in the Normal, Ischaemic and Failing Heart

Hypoxia decreases creatine uptake in cardiomyocytes, while creatine supplementation enhances HIF activation

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