Supranormal myocardial creatine and phosphocreatine concentrations lead to cardiac hypertrophy and heart failure

insights from creatine transporter-overexpressing transgenic mice

Julie Wallis, Craig A Lygate, Michiel ten Hove, A Fischer, Jürgen E Schneider, Liam Sebag-Montefiore, Dana Dawson, Karen Hulbert, Wen Zhang, Mei Hua Zhang , Hugh Watkins, Kieran Clarke, Stefan Neubauer

Research output: Contribution to journalArticle

68 Citations (Scopus)

Abstract

Background: Heart failure is associated with deranged cardiac energy metabolism, including reductions of creatine and phosphocreatine. Interventions that increase myocardial high-energy phosphate stores have been proposed as a strategy for treatment of heart failure. Previously, it has not been possible to increase myocardial creatine and phosphocreatine concentrations to supranormal levels because they are subject to tight regulation by the sarcolemmal creatine transporter (CrT).
Methods and Results: We therefore created 2 transgenic mouse lines overexpressing the myocardial creatine transporter (CrT-OE). Compared with wild-type (WT) littermate controls, total creatine (by high-performance liquid chromatography) was increased in CrT-OE hearts (66±6 nmol/mg protein in WT versus 133±52 nmol/mg protein in CrT-OE). Phosphocreatine levels (by 31P magnetic resonance spectroscopy) were also increased but to a lesser extent. Surprisingly, CrT-OE mice developed left ventricular (LV) dilatation (LV end-diastolic volume: 21.5±4.3 µL in WT versus 33.1±9.6 µL in CrT-OE; P=0.002), substantial LV dysfunction (ejection fraction: 64±9% in WT versus 49±13% in CrT-OE; range, 22% to 70%; P=0.003), and LV hypertrophy (by 3-dimensional echocardiography and magnetic resonance imaging). Myocardial creatine content correlated closely with LV end-diastolic volume (r=0.51, P=0.02), ejection fraction (r=-0.74, P=0.0002), LV weight (r=0.59, P=0.006), LV end-diastolic pressure (r=0.52, P=0.02), and dP/dtmax (r=-0.69, P=0.0008). Despite increased creatine and phosphocreatine levels, CrT-OE hearts showed energetic impairment, with increased free ADP concentrations and reduced free-energy change levels.
Conclusions: Overexpression of the CrT leads to supranormal levels of myocardial creatine and phosphocreatine, but the heart is incapable of keeping the augmented creatine pool adequately phosphorylated, resulting in increased free ADP levels, LV hypertrophy, and dysfunction. Our data demonstrate that a disturbance of the CrT-mediated tight regulation of cardiac energy metabolism has deleterious functional consequences. These findings caution against the uncritical use of creatine as a therapeutic agent in heart disease.
Original languageEnglish
Pages (from-to)3131-3139
Number of pages9
JournalCirculation
Volume112
Issue number20
DOIs
Publication statusPublished - 2005

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Phosphocreatine
Creatine
Cardiomegaly
Transgenic Mice
Heart Failure
Stroke Volume
Left Ventricular Dysfunction
Left Ventricular Hypertrophy
Adenosine Diphosphate
Energy Metabolism
creatine transporter
Treatment Failure
Echocardiography
Dilatation
Heart Diseases
Proteins
Magnetic Resonance Spectroscopy
Phosphates
High Pressure Liquid Chromatography
Magnetic Resonance Imaging

Keywords

  • animals
  • cardiomegaly
  • animal disease models
  • gene expression regulation
  • heart failure
  • membrane transport proteins
  • mice
  • transgenic mice
  • open reading frames
  • rabbits
  • sarcolemma
  • hypertrophy
  • spectroscopy
  • magnetic resonance imaging
  • metabolism

Cite this

Supranormal myocardial creatine and phosphocreatine concentrations lead to cardiac hypertrophy and heart failure : insights from creatine transporter-overexpressing transgenic mice. / Wallis, Julie; Lygate, Craig A; ten Hove, Michiel; Fischer, A; Schneider, Jürgen E; Sebag-Montefiore, Liam; Dawson, Dana; Hulbert, Karen; Zhang, Wen; Zhang , Mei Hua; Watkins, Hugh; Clarke, Kieran; Neubauer, Stefan.

In: Circulation, Vol. 112, No. 20, 2005, p. 3131-3139.

Research output: Contribution to journalArticle

Wallis, J, Lygate, CA, ten Hove, M, Fischer, A, Schneider, JE, Sebag-Montefiore, L, Dawson, D, Hulbert, K, Zhang, W, Zhang , MH, Watkins, H, Clarke, K & Neubauer, S 2005, 'Supranormal myocardial creatine and phosphocreatine concentrations lead to cardiac hypertrophy and heart failure: insights from creatine transporter-overexpressing transgenic mice', Circulation, vol. 112, no. 20, pp. 3131-3139. https://doi.org/10.1161/CIRCULATIONAHA.105.572990
Wallis, Julie ; Lygate, Craig A ; ten Hove, Michiel ; Fischer, A ; Schneider, Jürgen E ; Sebag-Montefiore, Liam ; Dawson, Dana ; Hulbert, Karen ; Zhang, Wen ; Zhang , Mei Hua ; Watkins, Hugh ; Clarke, Kieran ; Neubauer, Stefan. / Supranormal myocardial creatine and phosphocreatine concentrations lead to cardiac hypertrophy and heart failure : insights from creatine transporter-overexpressing transgenic mice. In: Circulation. 2005 ; Vol. 112, No. 20. pp. 3131-3139.
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abstract = "Background: Heart failure is associated with deranged cardiac energy metabolism, including reductions of creatine and phosphocreatine. Interventions that increase myocardial high-energy phosphate stores have been proposed as a strategy for treatment of heart failure. Previously, it has not been possible to increase myocardial creatine and phosphocreatine concentrations to supranormal levels because they are subject to tight regulation by the sarcolemmal creatine transporter (CrT). Methods and Results: We therefore created 2 transgenic mouse lines overexpressing the myocardial creatine transporter (CrT-OE). Compared with wild-type (WT) littermate controls, total creatine (by high-performance liquid chromatography) was increased in CrT-OE hearts (66±6 nmol/mg protein in WT versus 133±52 nmol/mg protein in CrT-OE). Phosphocreatine levels (by 31P magnetic resonance spectroscopy) were also increased but to a lesser extent. Surprisingly, CrT-OE mice developed left ventricular (LV) dilatation (LV end-diastolic volume: 21.5±4.3 µL in WT versus 33.1±9.6 µL in CrT-OE; P=0.002), substantial LV dysfunction (ejection fraction: 64±9{\%} in WT versus 49±13{\%} in CrT-OE; range, 22{\%} to 70{\%}; P=0.003), and LV hypertrophy (by 3-dimensional echocardiography and magnetic resonance imaging). Myocardial creatine content correlated closely with LV end-diastolic volume (r=0.51, P=0.02), ejection fraction (r=-0.74, P=0.0002), LV weight (r=0.59, P=0.006), LV end-diastolic pressure (r=0.52, P=0.02), and dP/dtmax (r=-0.69, P=0.0008). Despite increased creatine and phosphocreatine levels, CrT-OE hearts showed energetic impairment, with increased free ADP concentrations and reduced free-energy change levels. Conclusions: Overexpression of the CrT leads to supranormal levels of myocardial creatine and phosphocreatine, but the heart is incapable of keeping the augmented creatine pool adequately phosphorylated, resulting in increased free ADP levels, LV hypertrophy, and dysfunction. Our data demonstrate that a disturbance of the CrT-mediated tight regulation of cardiac energy metabolism has deleterious functional consequences. These findings caution against the uncritical use of creatine as a therapeutic agent in heart disease.",
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TY - JOUR

T1 - Supranormal myocardial creatine and phosphocreatine concentrations lead to cardiac hypertrophy and heart failure

T2 - insights from creatine transporter-overexpressing transgenic mice

AU - Wallis, Julie

AU - Lygate, Craig A

AU - ten Hove, Michiel

AU - Fischer, A

AU - Schneider, Jürgen E

AU - Sebag-Montefiore, Liam

AU - Dawson, Dana

AU - Hulbert, Karen

AU - Zhang, Wen

AU - Zhang , Mei Hua

AU - Watkins, Hugh

AU - Clarke, Kieran

AU - Neubauer, Stefan

PY - 2005

Y1 - 2005

N2 - Background: Heart failure is associated with deranged cardiac energy metabolism, including reductions of creatine and phosphocreatine. Interventions that increase myocardial high-energy phosphate stores have been proposed as a strategy for treatment of heart failure. Previously, it has not been possible to increase myocardial creatine and phosphocreatine concentrations to supranormal levels because they are subject to tight regulation by the sarcolemmal creatine transporter (CrT). Methods and Results: We therefore created 2 transgenic mouse lines overexpressing the myocardial creatine transporter (CrT-OE). Compared with wild-type (WT) littermate controls, total creatine (by high-performance liquid chromatography) was increased in CrT-OE hearts (66±6 nmol/mg protein in WT versus 133±52 nmol/mg protein in CrT-OE). Phosphocreatine levels (by 31P magnetic resonance spectroscopy) were also increased but to a lesser extent. Surprisingly, CrT-OE mice developed left ventricular (LV) dilatation (LV end-diastolic volume: 21.5±4.3 µL in WT versus 33.1±9.6 µL in CrT-OE; P=0.002), substantial LV dysfunction (ejection fraction: 64±9% in WT versus 49±13% in CrT-OE; range, 22% to 70%; P=0.003), and LV hypertrophy (by 3-dimensional echocardiography and magnetic resonance imaging). Myocardial creatine content correlated closely with LV end-diastolic volume (r=0.51, P=0.02), ejection fraction (r=-0.74, P=0.0002), LV weight (r=0.59, P=0.006), LV end-diastolic pressure (r=0.52, P=0.02), and dP/dtmax (r=-0.69, P=0.0008). Despite increased creatine and phosphocreatine levels, CrT-OE hearts showed energetic impairment, with increased free ADP concentrations and reduced free-energy change levels. Conclusions: Overexpression of the CrT leads to supranormal levels of myocardial creatine and phosphocreatine, but the heart is incapable of keeping the augmented creatine pool adequately phosphorylated, resulting in increased free ADP levels, LV hypertrophy, and dysfunction. Our data demonstrate that a disturbance of the CrT-mediated tight regulation of cardiac energy metabolism has deleterious functional consequences. These findings caution against the uncritical use of creatine as a therapeutic agent in heart disease.

AB - Background: Heart failure is associated with deranged cardiac energy metabolism, including reductions of creatine and phosphocreatine. Interventions that increase myocardial high-energy phosphate stores have been proposed as a strategy for treatment of heart failure. Previously, it has not been possible to increase myocardial creatine and phosphocreatine concentrations to supranormal levels because they are subject to tight regulation by the sarcolemmal creatine transporter (CrT). Methods and Results: We therefore created 2 transgenic mouse lines overexpressing the myocardial creatine transporter (CrT-OE). Compared with wild-type (WT) littermate controls, total creatine (by high-performance liquid chromatography) was increased in CrT-OE hearts (66±6 nmol/mg protein in WT versus 133±52 nmol/mg protein in CrT-OE). Phosphocreatine levels (by 31P magnetic resonance spectroscopy) were also increased but to a lesser extent. Surprisingly, CrT-OE mice developed left ventricular (LV) dilatation (LV end-diastolic volume: 21.5±4.3 µL in WT versus 33.1±9.6 µL in CrT-OE; P=0.002), substantial LV dysfunction (ejection fraction: 64±9% in WT versus 49±13% in CrT-OE; range, 22% to 70%; P=0.003), and LV hypertrophy (by 3-dimensional echocardiography and magnetic resonance imaging). Myocardial creatine content correlated closely with LV end-diastolic volume (r=0.51, P=0.02), ejection fraction (r=-0.74, P=0.0002), LV weight (r=0.59, P=0.006), LV end-diastolic pressure (r=0.52, P=0.02), and dP/dtmax (r=-0.69, P=0.0008). Despite increased creatine and phosphocreatine levels, CrT-OE hearts showed energetic impairment, with increased free ADP concentrations and reduced free-energy change levels. Conclusions: Overexpression of the CrT leads to supranormal levels of myocardial creatine and phosphocreatine, but the heart is incapable of keeping the augmented creatine pool adequately phosphorylated, resulting in increased free ADP levels, LV hypertrophy, and dysfunction. Our data demonstrate that a disturbance of the CrT-mediated tight regulation of cardiac energy metabolism has deleterious functional consequences. These findings caution against the uncritical use of creatine as a therapeutic agent in heart disease.

KW - animals

KW - cardiomegaly

KW - animal disease models

KW - gene expression regulation

KW - heart failure

KW - membrane transport proteins

KW - mice

KW - transgenic mice

KW - open reading frames

KW - rabbits

KW - sarcolemma

KW - hypertrophy

KW - spectroscopy

KW - magnetic resonance imaging

KW - metabolism

U2 - 10.1161/CIRCULATIONAHA.105.572990

DO - 10.1161/CIRCULATIONAHA.105.572990

M3 - Article

VL - 112

SP - 3131

EP - 3139

JO - Circulation

JF - Circulation

SN - 0009-7322

IS - 20

ER -