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Craig A. Lygate - One of the best experts on this subject based on the ideXlab platform.
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age dependent decline in cardiac function in Guanidinoacetate n methyltransferase knockout mice
Frontiers in Physiology, 2020Co-Authors: Dunja Aksentijevic, Sevasti Zervou, Debra J Mcandrew, Jurgen E Schneider, Thomas R Eykyn, Julie Wallis, Stefan Neubauer, Craig A. LygateAbstract:Aim: Guanidinoacetate N-Methyltransferase (GAMT) is the second essential enzyme in creatine (Cr) biosynthesis. Short-term Cr deficiency is metabolically well tolerated as GAMT-/- mice exhibit normal exercise capacity and response to ischemic heart failure. However, we hypothesized long-term consequences of Cr deficiency and/or accumulation of the Cr precursor Guanidinoacetate (GA). Methods: Cardiac function and metabolic profile were studied in GAMT-/- mice >1 year. Results: In vivo LV catheterization revealed lower heart rate and developed pressure in aging GAMT-/- but normal lung weight and survival versus age-matched controls. Electron microscopy indicated reduced mitochondrial volume density in GAMT-/- hearts (P < 0.001), corroborated by lower mtDNA copy number (P < 0.004), and citrate synthase activity (P < 0.05), however, without impaired mitochondrial respiration. Furthermore, myocardial energy stores and key ATP homeostatic enzymes were barely altered, while pathology was unrelated to oxidative stress since superoxide production and protein carbonylation were unaffected. Gene expression of PGC-1α was 2.5-fold higher in GAMT-/- hearts while downstream genes were not activated, implicating a dysfunction in mitochondrial biogenesis signaling. This was normalized by 10 days of dietary Cr supplementation, as were all in vivo functional parameters, however, it was not possible to differentiate whether relief from Cr deficiency or GA toxicity was causative. Conclusion: Long-term Cr deficiency in GAMT-/- mice reduces mitochondrial volume without affecting respiratory function, most likely due to impaired biogenesis. This is associated with hemodynamic changes without evidence of heart failure, which may represent an acceptable functional compromise in return for reduced energy demand in aging mice.
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age dependent decline in cardiac function in Guanidinoacetate n methyltransferase knockout mice
Frontiers in Physiology, 2020Co-Authors: Dunja Aksentijevic, Sevasti Zervou, Debra J Mcandrew, Jurgen E Schneider, Thomas R Eykyn, Julie Wallis, Stefan Neubauer, Craig A. LygateAbstract:Aim: Guanidinoacetate N-Methyltransferase (GAMT) is the second essential enzyme in creatine (Cr) biosynthesis. Short-term Cr deficiency is metabolically well tolerated as GAMT-/- mice exhibit normal exercise capacity and response to ischaemic heart failure. However, we hypothesised long-term consequences of Cr deficiency and/or accumulation of the Cr precursor Guanidinoacetate (GA). Methods: Cardiac function and metabolic profile were studied in GAMT-/- mice >1 year. Results: In vivo LV catheterisation revealed lower heart rate and developed pressure in ageing GAMT-/- but normal lung weight and survival versus age-matched controls. Electron microscopy indicated reduced mitochondrial volume density in GAMT-/- hearts (P<0.001), corroborated by lower mtDNA copy number (P<0.004), and citrate synthase activity (P<0.05) however without impaired mitochondrial respiration. Furthermore, myocardial energy stores and key ATP homeostatic enzymes were barely altered, while pathology was unrelated to oxidative stress since superoxide production and protein carbonylation were unaffected. Gene expression of PGC-1α was 2.5-fold higher in GAMT-/- hearts while downstream genes were not activated, implicating a dysfunction in mitochondrial biogenesis signalling. This was normalised by 10 days of dietary Cr supplementation, as were all in vivo functional parameters, however, it was not possible to differentiate whether relief from Cr deficiency or GA toxicity was causative. Conclusion: Long-term Cr deficiency in GAMT-/- mice reduces mitochondrial volume without affecting respiratory function, most likely due to impaired biogenesis. This is associated with haemodynamic changes without evidence of heart failure, which may represent an acceptable functional compromise in return for reduced energy demand in ageing mice.
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living without creatine unchanged exercise capacity and response to chronic myocardial infarction in creatine deficient mice
Circulation Research, 2013Co-Authors: Craig A. Lygate, Liam Sebagmontefiore, Dunja Aksentijevic, Debra J Medway, Dana Dawson, Ten M Hove, Darci Phillips, J De Bono, Imre Hunyor, Keith M ChannonAbstract: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 (>10km/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 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 pre-cursor 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.
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compensation for impaired myocardial phosphotransfer in Guanidinoacetate n methyltransferase knockout mice
Heart, 2010Co-Authors: Dunja Aksentijevic, Liam Sebagmontefiore, Debra J Medway, K Makinen, Craig A. Lygate, Stefan NeubauerAbstract:Guanidinoacetate-N-Methyltransferase (GAMT) is a key enzyme in creatine biosynthesis, such that GAMT knockout mice lack phosphocreatine (PCr) as a substrate for energy transfer via the creatine kinase (CK) reaction. Despite undetectable levels of PCr and creatine, GAMT knockout mice exhibit only minor changes in baseline function and impaired contractile reserve, …
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cardiac structure and function during ageing in energetically compromised Guanidinoacetate n methyltransferase gamt knockout mice a one year longitudinal mri study
Journal of Cardiovascular Magnetic Resonance, 2008Co-Authors: Jurgen E Schneider, Hugh Watkins, Kieran Clarke, Michiel Ten Hove, Dirk Isbrandt, Craig A. Lygate, Leeanne Stork, Jordana T Bell, Stefan NeubauerAbstract:High-resolution magnetic resonance imaging (cine-MRI) is well suited for determining global cardiac function longitudinally in genetically or surgically manipulated mice, but in practice it is seldom used to its full potential. In this study, male and female Guanidinoacetate N-Methyltransferase (GAMT) knockout, and wild type littermate mice were subjected to a longitudinal cine-MRI study at four time points over the course of one year. GAMT is an essential enzyme in creatine biosynthesis, such that GAMT deficient mice are entirely creatine-free. Since creatine plays an important role in the buffering and transfer of high-energy phosphate bonds in the heart, it was hypothesized that lack of creatine would be detrimental for resting cardiac performance during ageing. Measurements of cardiac structure (left ventricular mass and volumes) and function (ejection fraction, stroke volume, cardiac output) were obtained using high-resolution cine-MRI at 9.4 T under isoflurane anaesthesia. There were no physiologically significant differences in cardiac function between wild type and GAMT knockout mice at any time point for male or female groups, or for both combined (for example ejection fraction: 6 weeks (KO vs. WT): 70 ± 6% vs. 65 ± 7%; 4 months: 70 ± 6% vs. 62 ± 8%; 8 months: 62 ± 11% vs. 62 ± 6%; 12 months: 61 ± 7% vs. 59 ± 11%, respectively). These findings suggest the presence of comprehensive adaptations in the knockout mice that can compensate for a lack of creatine. Furthermore, this study clearly demonstrates the power of cine-MRI for accurate non-invasive, serial cardiac measurements. Cardiac growth curves could easily be defined for each group, in the same set of animals for all time points, providing improved statistical power, and substantially reducing the number of mice required to conduct such a study. This technique should be eminently useful for following changes of cardiac structure and function during ageing.
Dirk Isbrandt - One of the best experts on this subject based on the ideXlab platform.
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A Mouse Model of Creatine Transporter Deficiency Reveals Impaired Motor Function and Muscle Energy Metabolism
Frontiers Media S.A., 2018Co-Authors: Malte Stockebrand, Ali Sasani, Devashish Das, Sönke Hornig, Irm Hermans-borgmeyer, Hannah A. Lake, Dirk IsbrandtAbstract:Creatine serves as fast energy buffer in organs of high-energy demand such as brain and skeletal muscle. L-Arginine:glycine amidinotransferase (AGAT) and Guanidinoacetate N-Methyltransferase are responsible for endogenous creatine synthesis. Subsequent uptake into target organs like skeletal muscle, heart and brain is mediated by the creatine transporter (CT1, SLC6A8). Creatine deficiency syndromes are caused by defects of endogenous creatine synthesis or transport and are mainly characterized by intellectual disability, behavioral abnormalities, poorly developed muscle mass, and in some cases also muscle weakness. CT1-deficiency is estimated to be among the most common causes of X-linked intellectual disability and therefore the brain phenotype was the main focus of recent research. Unfortunately, very limited data concerning muscle creatine levels and functions are available from patients with CT1 deficiency. Furthermore, different CT1-deficient mouse models yielded conflicting results and detailed analyses of their muscular phenotype are lacking. Here, we report the generation of a novel CT1-deficient mouse model and characterized the effects of creatine depletion in skeletal muscle. HPLC-analysis showed strongly reduced total creatine levels in skeletal muscle and heart. MR-spectroscopy revealed an almost complete absence of phosphocreatine in skeletal muscle. Increased AGAT expression in skeletal muscle was not sufficient to compensate for insufficient creatine transport. CT1-deficient mice displayed profound impairment of skeletal muscle function and morphology (i.e., reduced strength, reduced endurance, and muscle atrophy). Furthermore, severely altered energy homeostasis was evident on magnetic resonance spectroscopy. Strongly reduced phosphocreatine resulted in decreased ATP/Pi levels despite an increased inorganic phosphate to ATP flux. Concerning glucose metabolism, we show increased glucose transporter type 4 expression in muscle and improved glucose clearance in CT1-deficient mice. These metabolic changes were associated with activation of AMP-activated protein kinase – a central regulator of energy homeostasis. In summary, creatine transporter deficiency resulted in a severe muscle weakness and atrophy despite different compensatory mechanisms
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cardiac structure and function during ageing in energetically compromised Guanidinoacetate n methyltransferase gamt knockout mice a one year longitudinal mri study
Journal of Cardiovascular Magnetic Resonance, 2008Co-Authors: Jurgen E Schneider, Hugh Watkins, Kieran Clarke, Michiel Ten Hove, Dirk Isbrandt, Craig A. Lygate, Leeanne Stork, Jordana T Bell, Stefan NeubauerAbstract:High-resolution magnetic resonance imaging (cine-MRI) is well suited for determining global cardiac function longitudinally in genetically or surgically manipulated mice, but in practice it is seldom used to its full potential. In this study, male and female Guanidinoacetate N-Methyltransferase (GAMT) knockout, and wild type littermate mice were subjected to a longitudinal cine-MRI study at four time points over the course of one year. GAMT is an essential enzyme in creatine biosynthesis, such that GAMT deficient mice are entirely creatine-free. Since creatine plays an important role in the buffering and transfer of high-energy phosphate bonds in the heart, it was hypothesized that lack of creatine would be detrimental for resting cardiac performance during ageing. Measurements of cardiac structure (left ventricular mass and volumes) and function (ejection fraction, stroke volume, cardiac output) were obtained using high-resolution cine-MRI at 9.4 T under isoflurane anaesthesia. There were no physiologically significant differences in cardiac function between wild type and GAMT knockout mice at any time point for male or female groups, or for both combined (for example ejection fraction: 6 weeks (KO vs. WT): 70 ± 6% vs. 65 ± 7%; 4 months: 70 ± 6% vs. 62 ± 8%; 8 months: 62 ± 11% vs. 62 ± 6%; 12 months: 61 ± 7% vs. 59 ± 11%, respectively). These findings suggest the presence of comprehensive adaptations in the knockout mice that can compensate for a lack of creatine. Furthermore, this study clearly demonstrates the power of cine-MRI for accurate non-invasive, serial cardiac measurements. Cardiac growth curves could easily be defined for each group, in the same set of animals for all time points, providing improved statistical power, and substantially reducing the number of mice required to conduct such a study. This technique should be eminently useful for following changes of cardiac structure and function during ageing.
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cardiac structure and function during ageing in energetically compromised Guanidinoacetate n methyltransferase gamt knockout mice a one year longitudinal mri study
Journal of Cardiovascular Magnetic Resonance, 2008Co-Authors: Jurgen E Schneider, Hugh Watkins, Kieran Clarke, Michiel Ten Hove, Dirk Isbrandt, Craig A. Lygate, Leeanne Stork, Jordana T Bell, Stefan NeubauerAbstract:Background: High-resolution magnetic resonance imaging (cine-MRI) is well suited for determining global cardiac function longitudinally in genetically or surgically manipulated mice, but in practice it is seldom used to its full potential. In this study, male and female Guanidinoacetate N-Methyltransferase (GAMT) knockout, and wild type littermate mice were subjected to a longitudinal cine-MRI study at four time points over the course of one year. GAMT is an essential enzyme in creatine biosynthesis, such that GAMT deficient mice are entirely creatine-free. Since creatine plays an important role in the buffering and transfer of high-energy phosphate bonds in the heart, it was hypothesized that lack of creatine would be detrimental for resting cardiac performance during ageing. Methods: Measurements of cardiac structure (left ventricular mass and volumes) and function (ejection fraction, stroke volume, cardiac output) were obtained using high-resolution cine-MRI at 9.4 T under isoflurane anaesthesia. Results: There were no physiologically significant differences in cardiac function between wild type and GAMT knockout mice at any time point for male or female groups, or for both combined (for example ejection fraction: 6 weeks (KO vs. WT): 70 ± 6% vs. 65 ± 7%; 4 months: 70 ± 6% vs. 62 ± 8%; 8 months: 62 ± 11% vs. 62 ± 6%; 12 months: 61 ± 7% vs. 59 ± 11%, respectively). Conclusion: These findings suggest the presence of comprehensive adaptations in the knockout mice that can compensate for a lack of creatine. Furthermore, this study clearly demonstrates the power of cineMRI for accurate non-invasive, serial cardiac measurements. Cardiac growth curves could easily be defined for each group, in the same set of animals for all time points, providing improved statistical power, and substantially reducing the number of mice required to conduct such a study. This technique should be eminently useful for following changes of cardiac structure and function during ageing.
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reduced inotropic reserve and increased susceptibility to cardiac ischemia reperfusion injury in phosphocreatine deficient Guanidinoacetate n methyltransferase knockout mice
Circulation, 2005Co-Authors: Michiel Ten Hove, Elisabeth A Sang, Karen Hulbert, Liam Sebagmontefiore, Jurgen E Schneider, Hugh Watkins, Kieran Clarke, Alexandra Fischer, Craig A. Lygate, Dirk IsbrandtAbstract:Background— The role of the creatine kinase (CK)/phosphocreatine (PCr) energy buffer and transport system in heart remains unclear. Guanidinoacetate-N-Methyltransferase–knockout (GAMT−/−) mice represent a new model of profoundly altered cardiac energetics, showing undetectable levels of PCr and creatine and accumulation of the precursor (phospho-)Guanidinoacetate (P-GA). To characterize the role of a substantially impaired CK/PCr system in heart, we studied the cardiac phenotype of wild-type (WT) and GAMT−/− mice. Methods and Results— GAMT−/− mice did not show cardiac hypertrophy (myocyte cross-sectional areas, hypertrophy markers atrial natriuretic factor and β-myosin heavy chain). Systolic and diastolic function, measured invasively (left ventricular conductance catheter) and noninvasively (MRI), were similar for WT and GAMT−/− mice. However, during inotropic stimulation with dobutamine, preload-recruitable stroke work failed to reach maximal levels of performance in GAMT−/− hearts (101±8 mm Hg in WT ve...
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biochemical and behavioural phenotyping of a mouse model for gamt deficiency
Journal of the Neurological Sciences, 2005Co-Authors: A Torremans, Dirk Isbrandt, B. Marescau, I Possemiers, Rudi Dhooge, Peter Paul De DeynAbstract:Abstract Deficiency of Guanidinoacetate N-Methyltransferase (GAMT) is the first described creatine (CT) deficiency syndrome in man, biochemically characterized by accumulation of guanidinoacetic acid (GAA) and depletion of CT. Patients exhibit severe developmental and muscular problems. We created a mouse model for GAMT deficiency, which exerts biochemical changes comparable with those found in human GAMT-deficient subjects. CT and creatinine (CTN) levels are significantly decreased and GAA is increased in knockout (KO) mice. In patients, other guanidino compounds (GCs) appear to be altered as well, which may also contribute to the symptomatology. Extensive evaluation of GCs levels in the GAMT mouse model was therefore considered appropriate. Concentrations of 13 GCs in plasma, 24-h urine, brain and muscle of GAMT mice were measured. We also report on the detailed behavioural characterization of this model for GAMT deficiency. Besides an increase of GAA and a decrease of CT and CTN in plasma, 24-h urine, brain and muscle of KO mice, we observed a significant increase of other GCs in brain and muscle that was sometimes reflected in plasma and/or urine. KO mice displayed mild cognitive impairment. In general, it could be concluded that the GAMT mouse model is very useful for biochemical research of GAMT deficiency, but shows only a mild cognitive deficit.
Stefan Neubauer - One of the best experts on this subject based on the ideXlab platform.
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age dependent decline in cardiac function in Guanidinoacetate n methyltransferase knockout mice
Frontiers in Physiology, 2020Co-Authors: Dunja Aksentijevic, Sevasti Zervou, Debra J Mcandrew, Jurgen E Schneider, Thomas R Eykyn, Julie Wallis, Stefan Neubauer, Craig A. LygateAbstract:Aim: Guanidinoacetate N-Methyltransferase (GAMT) is the second essential enzyme in creatine (Cr) biosynthesis. Short-term Cr deficiency is metabolically well tolerated as GAMT-/- mice exhibit normal exercise capacity and response to ischaemic heart failure. However, we hypothesised long-term consequences of Cr deficiency and/or accumulation of the Cr precursor Guanidinoacetate (GA). Methods: Cardiac function and metabolic profile were studied in GAMT-/- mice >1 year. Results: In vivo LV catheterisation revealed lower heart rate and developed pressure in ageing GAMT-/- but normal lung weight and survival versus age-matched controls. Electron microscopy indicated reduced mitochondrial volume density in GAMT-/- hearts (P<0.001), corroborated by lower mtDNA copy number (P<0.004), and citrate synthase activity (P<0.05) however without impaired mitochondrial respiration. Furthermore, myocardial energy stores and key ATP homeostatic enzymes were barely altered, while pathology was unrelated to oxidative stress since superoxide production and protein carbonylation were unaffected. Gene expression of PGC-1α was 2.5-fold higher in GAMT-/- hearts while downstream genes were not activated, implicating a dysfunction in mitochondrial biogenesis signalling. This was normalised by 10 days of dietary Cr supplementation, as were all in vivo functional parameters, however, it was not possible to differentiate whether relief from Cr deficiency or GA toxicity was causative. Conclusion: Long-term Cr deficiency in GAMT-/- mice reduces mitochondrial volume without affecting respiratory function, most likely due to impaired biogenesis. This is associated with haemodynamic changes without evidence of heart failure, which may represent an acceptable functional compromise in return for reduced energy demand in ageing mice.
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age dependent decline in cardiac function in Guanidinoacetate n methyltransferase knockout mice
Frontiers in Physiology, 2020Co-Authors: Dunja Aksentijevic, Sevasti Zervou, Debra J Mcandrew, Jurgen E Schneider, Thomas R Eykyn, Julie Wallis, Stefan Neubauer, Craig A. LygateAbstract:Aim: Guanidinoacetate N-Methyltransferase (GAMT) is the second essential enzyme in creatine (Cr) biosynthesis. Short-term Cr deficiency is metabolically well tolerated as GAMT-/- mice exhibit normal exercise capacity and response to ischemic heart failure. However, we hypothesized long-term consequences of Cr deficiency and/or accumulation of the Cr precursor Guanidinoacetate (GA). Methods: Cardiac function and metabolic profile were studied in GAMT-/- mice >1 year. Results: In vivo LV catheterization revealed lower heart rate and developed pressure in aging GAMT-/- but normal lung weight and survival versus age-matched controls. Electron microscopy indicated reduced mitochondrial volume density in GAMT-/- hearts (P < 0.001), corroborated by lower mtDNA copy number (P < 0.004), and citrate synthase activity (P < 0.05), however, without impaired mitochondrial respiration. Furthermore, myocardial energy stores and key ATP homeostatic enzymes were barely altered, while pathology was unrelated to oxidative stress since superoxide production and protein carbonylation were unaffected. Gene expression of PGC-1α was 2.5-fold higher in GAMT-/- hearts while downstream genes were not activated, implicating a dysfunction in mitochondrial biogenesis signaling. This was normalized by 10 days of dietary Cr supplementation, as were all in vivo functional parameters, however, it was not possible to differentiate whether relief from Cr deficiency or GA toxicity was causative. Conclusion: Long-term Cr deficiency in GAMT-/- mice reduces mitochondrial volume without affecting respiratory function, most likely due to impaired biogenesis. This is associated with hemodynamic changes without evidence of heart failure, which may represent an acceptable functional compromise in return for reduced energy demand in aging mice.
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compensation for impaired myocardial phosphotransfer in Guanidinoacetate n methyltransferase knockout mice
Heart, 2010Co-Authors: Dunja Aksentijevic, Liam Sebagmontefiore, Debra J Medway, K Makinen, Craig A. Lygate, Stefan NeubauerAbstract:Guanidinoacetate-N-Methyltransferase (GAMT) is a key enzyme in creatine biosynthesis, such that GAMT knockout mice lack phosphocreatine (PCr) as a substrate for energy transfer via the creatine kinase (CK) reaction. Despite undetectable levels of PCr and creatine, GAMT knockout mice exhibit only minor changes in baseline function and impaired contractile reserve, …
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cardiac structure and function during ageing in energetically compromised Guanidinoacetate n methyltransferase gamt knockout mice a one year longitudinal mri study
Journal of Cardiovascular Magnetic Resonance, 2008Co-Authors: Jurgen E Schneider, Hugh Watkins, Kieran Clarke, Michiel Ten Hove, Dirk Isbrandt, Craig A. Lygate, Leeanne Stork, Jordana T Bell, Stefan NeubauerAbstract:High-resolution magnetic resonance imaging (cine-MRI) is well suited for determining global cardiac function longitudinally in genetically or surgically manipulated mice, but in practice it is seldom used to its full potential. In this study, male and female Guanidinoacetate N-Methyltransferase (GAMT) knockout, and wild type littermate mice were subjected to a longitudinal cine-MRI study at four time points over the course of one year. GAMT is an essential enzyme in creatine biosynthesis, such that GAMT deficient mice are entirely creatine-free. Since creatine plays an important role in the buffering and transfer of high-energy phosphate bonds in the heart, it was hypothesized that lack of creatine would be detrimental for resting cardiac performance during ageing. Measurements of cardiac structure (left ventricular mass and volumes) and function (ejection fraction, stroke volume, cardiac output) were obtained using high-resolution cine-MRI at 9.4 T under isoflurane anaesthesia. There were no physiologically significant differences in cardiac function between wild type and GAMT knockout mice at any time point for male or female groups, or for both combined (for example ejection fraction: 6 weeks (KO vs. WT): 70 ± 6% vs. 65 ± 7%; 4 months: 70 ± 6% vs. 62 ± 8%; 8 months: 62 ± 11% vs. 62 ± 6%; 12 months: 61 ± 7% vs. 59 ± 11%, respectively). These findings suggest the presence of comprehensive adaptations in the knockout mice that can compensate for a lack of creatine. Furthermore, this study clearly demonstrates the power of cine-MRI for accurate non-invasive, serial cardiac measurements. Cardiac growth curves could easily be defined for each group, in the same set of animals for all time points, providing improved statistical power, and substantially reducing the number of mice required to conduct such a study. This technique should be eminently useful for following changes of cardiac structure and function during ageing.
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cardiac structure and function during ageing in energetically compromised Guanidinoacetate n methyltransferase gamt knockout mice a one year longitudinal mri study
Journal of Cardiovascular Magnetic Resonance, 2008Co-Authors: Jurgen E Schneider, Hugh Watkins, Kieran Clarke, Michiel Ten Hove, Dirk Isbrandt, Craig A. Lygate, Leeanne Stork, Jordana T Bell, Stefan NeubauerAbstract:Background: High-resolution magnetic resonance imaging (cine-MRI) is well suited for determining global cardiac function longitudinally in genetically or surgically manipulated mice, but in practice it is seldom used to its full potential. In this study, male and female Guanidinoacetate N-Methyltransferase (GAMT) knockout, and wild type littermate mice were subjected to a longitudinal cine-MRI study at four time points over the course of one year. GAMT is an essential enzyme in creatine biosynthesis, such that GAMT deficient mice are entirely creatine-free. Since creatine plays an important role in the buffering and transfer of high-energy phosphate bonds in the heart, it was hypothesized that lack of creatine would be detrimental for resting cardiac performance during ageing. Methods: Measurements of cardiac structure (left ventricular mass and volumes) and function (ejection fraction, stroke volume, cardiac output) were obtained using high-resolution cine-MRI at 9.4 T under isoflurane anaesthesia. Results: There were no physiologically significant differences in cardiac function between wild type and GAMT knockout mice at any time point for male or female groups, or for both combined (for example ejection fraction: 6 weeks (KO vs. WT): 70 ± 6% vs. 65 ± 7%; 4 months: 70 ± 6% vs. 62 ± 8%; 8 months: 62 ± 11% vs. 62 ± 6%; 12 months: 61 ± 7% vs. 59 ± 11%, respectively). Conclusion: These findings suggest the presence of comprehensive adaptations in the knockout mice that can compensate for a lack of creatine. Furthermore, this study clearly demonstrates the power of cineMRI for accurate non-invasive, serial cardiac measurements. Cardiac growth curves could easily be defined for each group, in the same set of animals for all time points, providing improved statistical power, and substantially reducing the number of mice required to conduct such a study. This technique should be eminently useful for following changes of cardiac structure and function during ageing.
Jurgen E Schneider - One of the best experts on this subject based on the ideXlab platform.
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age dependent decline in cardiac function in Guanidinoacetate n methyltransferase knockout mice
Frontiers in Physiology, 2020Co-Authors: Dunja Aksentijevic, Sevasti Zervou, Debra J Mcandrew, Jurgen E Schneider, Thomas R Eykyn, Julie Wallis, Stefan Neubauer, Craig A. LygateAbstract:Aim: Guanidinoacetate N-Methyltransferase (GAMT) is the second essential enzyme in creatine (Cr) biosynthesis. Short-term Cr deficiency is metabolically well tolerated as GAMT-/- mice exhibit normal exercise capacity and response to ischaemic heart failure. However, we hypothesised long-term consequences of Cr deficiency and/or accumulation of the Cr precursor Guanidinoacetate (GA). Methods: Cardiac function and metabolic profile were studied in GAMT-/- mice >1 year. Results: In vivo LV catheterisation revealed lower heart rate and developed pressure in ageing GAMT-/- but normal lung weight and survival versus age-matched controls. Electron microscopy indicated reduced mitochondrial volume density in GAMT-/- hearts (P<0.001), corroborated by lower mtDNA copy number (P<0.004), and citrate synthase activity (P<0.05) however without impaired mitochondrial respiration. Furthermore, myocardial energy stores and key ATP homeostatic enzymes were barely altered, while pathology was unrelated to oxidative stress since superoxide production and protein carbonylation were unaffected. Gene expression of PGC-1α was 2.5-fold higher in GAMT-/- hearts while downstream genes were not activated, implicating a dysfunction in mitochondrial biogenesis signalling. This was normalised by 10 days of dietary Cr supplementation, as were all in vivo functional parameters, however, it was not possible to differentiate whether relief from Cr deficiency or GA toxicity was causative. Conclusion: Long-term Cr deficiency in GAMT-/- mice reduces mitochondrial volume without affecting respiratory function, most likely due to impaired biogenesis. This is associated with haemodynamic changes without evidence of heart failure, which may represent an acceptable functional compromise in return for reduced energy demand in ageing mice.
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age dependent decline in cardiac function in Guanidinoacetate n methyltransferase knockout mice
Frontiers in Physiology, 2020Co-Authors: Dunja Aksentijevic, Sevasti Zervou, Debra J Mcandrew, Jurgen E Schneider, Thomas R Eykyn, Julie Wallis, Stefan Neubauer, Craig A. LygateAbstract:Aim: Guanidinoacetate N-Methyltransferase (GAMT) is the second essential enzyme in creatine (Cr) biosynthesis. Short-term Cr deficiency is metabolically well tolerated as GAMT-/- mice exhibit normal exercise capacity and response to ischemic heart failure. However, we hypothesized long-term consequences of Cr deficiency and/or accumulation of the Cr precursor Guanidinoacetate (GA). Methods: Cardiac function and metabolic profile were studied in GAMT-/- mice >1 year. Results: In vivo LV catheterization revealed lower heart rate and developed pressure in aging GAMT-/- but normal lung weight and survival versus age-matched controls. Electron microscopy indicated reduced mitochondrial volume density in GAMT-/- hearts (P < 0.001), corroborated by lower mtDNA copy number (P < 0.004), and citrate synthase activity (P < 0.05), however, without impaired mitochondrial respiration. Furthermore, myocardial energy stores and key ATP homeostatic enzymes were barely altered, while pathology was unrelated to oxidative stress since superoxide production and protein carbonylation were unaffected. Gene expression of PGC-1α was 2.5-fold higher in GAMT-/- hearts while downstream genes were not activated, implicating a dysfunction in mitochondrial biogenesis signaling. This was normalized by 10 days of dietary Cr supplementation, as were all in vivo functional parameters, however, it was not possible to differentiate whether relief from Cr deficiency or GA toxicity was causative. Conclusion: Long-term Cr deficiency in GAMT-/- mice reduces mitochondrial volume without affecting respiratory function, most likely due to impaired biogenesis. This is associated with hemodynamic changes without evidence of heart failure, which may represent an acceptable functional compromise in return for reduced energy demand in aging mice.
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cardiac structure and function during ageing in energetically compromised Guanidinoacetate n methyltransferase gamt knockout mice a one year longitudinal mri study
Journal of Cardiovascular Magnetic Resonance, 2008Co-Authors: Jurgen E Schneider, Hugh Watkins, Kieran Clarke, Michiel Ten Hove, Dirk Isbrandt, Craig A. Lygate, Leeanne Stork, Jordana T Bell, Stefan NeubauerAbstract:High-resolution magnetic resonance imaging (cine-MRI) is well suited for determining global cardiac function longitudinally in genetically or surgically manipulated mice, but in practice it is seldom used to its full potential. In this study, male and female Guanidinoacetate N-Methyltransferase (GAMT) knockout, and wild type littermate mice were subjected to a longitudinal cine-MRI study at four time points over the course of one year. GAMT is an essential enzyme in creatine biosynthesis, such that GAMT deficient mice are entirely creatine-free. Since creatine plays an important role in the buffering and transfer of high-energy phosphate bonds in the heart, it was hypothesized that lack of creatine would be detrimental for resting cardiac performance during ageing. Measurements of cardiac structure (left ventricular mass and volumes) and function (ejection fraction, stroke volume, cardiac output) were obtained using high-resolution cine-MRI at 9.4 T under isoflurane anaesthesia. There were no physiologically significant differences in cardiac function between wild type and GAMT knockout mice at any time point for male or female groups, or for both combined (for example ejection fraction: 6 weeks (KO vs. WT): 70 ± 6% vs. 65 ± 7%; 4 months: 70 ± 6% vs. 62 ± 8%; 8 months: 62 ± 11% vs. 62 ± 6%; 12 months: 61 ± 7% vs. 59 ± 11%, respectively). These findings suggest the presence of comprehensive adaptations in the knockout mice that can compensate for a lack of creatine. Furthermore, this study clearly demonstrates the power of cine-MRI for accurate non-invasive, serial cardiac measurements. Cardiac growth curves could easily be defined for each group, in the same set of animals for all time points, providing improved statistical power, and substantially reducing the number of mice required to conduct such a study. This technique should be eminently useful for following changes of cardiac structure and function during ageing.
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cardiac structure and function during ageing in energetically compromised Guanidinoacetate n methyltransferase gamt knockout mice a one year longitudinal mri study
Journal of Cardiovascular Magnetic Resonance, 2008Co-Authors: Jurgen E Schneider, Hugh Watkins, Kieran Clarke, Michiel Ten Hove, Dirk Isbrandt, Craig A. Lygate, Leeanne Stork, Jordana T Bell, Stefan NeubauerAbstract:Background: High-resolution magnetic resonance imaging (cine-MRI) is well suited for determining global cardiac function longitudinally in genetically or surgically manipulated mice, but in practice it is seldom used to its full potential. In this study, male and female Guanidinoacetate N-Methyltransferase (GAMT) knockout, and wild type littermate mice were subjected to a longitudinal cine-MRI study at four time points over the course of one year. GAMT is an essential enzyme in creatine biosynthesis, such that GAMT deficient mice are entirely creatine-free. Since creatine plays an important role in the buffering and transfer of high-energy phosphate bonds in the heart, it was hypothesized that lack of creatine would be detrimental for resting cardiac performance during ageing. Methods: Measurements of cardiac structure (left ventricular mass and volumes) and function (ejection fraction, stroke volume, cardiac output) were obtained using high-resolution cine-MRI at 9.4 T under isoflurane anaesthesia. Results: There were no physiologically significant differences in cardiac function between wild type and GAMT knockout mice at any time point for male or female groups, or for both combined (for example ejection fraction: 6 weeks (KO vs. WT): 70 ± 6% vs. 65 ± 7%; 4 months: 70 ± 6% vs. 62 ± 8%; 8 months: 62 ± 11% vs. 62 ± 6%; 12 months: 61 ± 7% vs. 59 ± 11%, respectively). Conclusion: These findings suggest the presence of comprehensive adaptations in the knockout mice that can compensate for a lack of creatine. Furthermore, this study clearly demonstrates the power of cineMRI for accurate non-invasive, serial cardiac measurements. Cardiac growth curves could easily be defined for each group, in the same set of animals for all time points, providing improved statistical power, and substantially reducing the number of mice required to conduct such a study. This technique should be eminently useful for following changes of cardiac structure and function during ageing.
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reduced inotropic reserve and increased susceptibility to cardiac ischemia reperfusion injury in phosphocreatine deficient Guanidinoacetate n methyltransferase knockout mice
Circulation, 2005Co-Authors: Michiel Ten Hove, Elisabeth A Sang, Karen Hulbert, Liam Sebagmontefiore, Jurgen E Schneider, Hugh Watkins, Kieran Clarke, Alexandra Fischer, Craig A. Lygate, Dirk IsbrandtAbstract:Background— The role of the creatine kinase (CK)/phosphocreatine (PCr) energy buffer and transport system in heart remains unclear. Guanidinoacetate-N-Methyltransferase–knockout (GAMT−/−) mice represent a new model of profoundly altered cardiac energetics, showing undetectable levels of PCr and creatine and accumulation of the precursor (phospho-)Guanidinoacetate (P-GA). To characterize the role of a substantially impaired CK/PCr system in heart, we studied the cardiac phenotype of wild-type (WT) and GAMT−/− mice. Methods and Results— GAMT−/− mice did not show cardiac hypertrophy (myocyte cross-sectional areas, hypertrophy markers atrial natriuretic factor and β-myosin heavy chain). Systolic and diastolic function, measured invasively (left ventricular conductance catheter) and noninvasively (MRI), were similar for WT and GAMT−/− mice. However, during inotropic stimulation with dobutamine, preload-recruitable stroke work failed to reach maximal levels of performance in GAMT−/− hearts (101±8 mm Hg in WT ve...
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age dependent decline in cardiac function in Guanidinoacetate n methyltransferase knockout mice
Frontiers in Physiology, 2020Co-Authors: Dunja Aksentijevic, Sevasti Zervou, Debra J Mcandrew, Jurgen E Schneider, Thomas R Eykyn, Julie Wallis, Stefan Neubauer, Craig A. LygateAbstract:Aim: Guanidinoacetate N-Methyltransferase (GAMT) is the second essential enzyme in creatine (Cr) biosynthesis. Short-term Cr deficiency is metabolically well tolerated as GAMT-/- mice exhibit normal exercise capacity and response to ischaemic heart failure. However, we hypothesised long-term consequences of Cr deficiency and/or accumulation of the Cr precursor Guanidinoacetate (GA). Methods: Cardiac function and metabolic profile were studied in GAMT-/- mice >1 year. Results: In vivo LV catheterisation revealed lower heart rate and developed pressure in ageing GAMT-/- but normal lung weight and survival versus age-matched controls. Electron microscopy indicated reduced mitochondrial volume density in GAMT-/- hearts (P<0.001), corroborated by lower mtDNA copy number (P<0.004), and citrate synthase activity (P<0.05) however without impaired mitochondrial respiration. Furthermore, myocardial energy stores and key ATP homeostatic enzymes were barely altered, while pathology was unrelated to oxidative stress since superoxide production and protein carbonylation were unaffected. Gene expression of PGC-1α was 2.5-fold higher in GAMT-/- hearts while downstream genes were not activated, implicating a dysfunction in mitochondrial biogenesis signalling. This was normalised by 10 days of dietary Cr supplementation, as were all in vivo functional parameters, however, it was not possible to differentiate whether relief from Cr deficiency or GA toxicity was causative. Conclusion: Long-term Cr deficiency in GAMT-/- mice reduces mitochondrial volume without affecting respiratory function, most likely due to impaired biogenesis. This is associated with haemodynamic changes without evidence of heart failure, which may represent an acceptable functional compromise in return for reduced energy demand in ageing mice.
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age dependent decline in cardiac function in Guanidinoacetate n methyltransferase knockout mice
Frontiers in Physiology, 2020Co-Authors: Dunja Aksentijevic, Sevasti Zervou, Debra J Mcandrew, Jurgen E Schneider, Thomas R Eykyn, Julie Wallis, Stefan Neubauer, Craig A. LygateAbstract:Aim: Guanidinoacetate N-Methyltransferase (GAMT) is the second essential enzyme in creatine (Cr) biosynthesis. Short-term Cr deficiency is metabolically well tolerated as GAMT-/- mice exhibit normal exercise capacity and response to ischemic heart failure. However, we hypothesized long-term consequences of Cr deficiency and/or accumulation of the Cr precursor Guanidinoacetate (GA). Methods: Cardiac function and metabolic profile were studied in GAMT-/- mice >1 year. Results: In vivo LV catheterization revealed lower heart rate and developed pressure in aging GAMT-/- but normal lung weight and survival versus age-matched controls. Electron microscopy indicated reduced mitochondrial volume density in GAMT-/- hearts (P < 0.001), corroborated by lower mtDNA copy number (P < 0.004), and citrate synthase activity (P < 0.05), however, without impaired mitochondrial respiration. Furthermore, myocardial energy stores and key ATP homeostatic enzymes were barely altered, while pathology was unrelated to oxidative stress since superoxide production and protein carbonylation were unaffected. Gene expression of PGC-1α was 2.5-fold higher in GAMT-/- hearts while downstream genes were not activated, implicating a dysfunction in mitochondrial biogenesis signaling. This was normalized by 10 days of dietary Cr supplementation, as were all in vivo functional parameters, however, it was not possible to differentiate whether relief from Cr deficiency or GA toxicity was causative. Conclusion: Long-term Cr deficiency in GAMT-/- mice reduces mitochondrial volume without affecting respiratory function, most likely due to impaired biogenesis. This is associated with hemodynamic changes without evidence of heart failure, which may represent an acceptable functional compromise in return for reduced energy demand in aging mice.
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living without creatine unchanged exercise capacity and response to chronic myocardial infarction in creatine deficient mice
Circulation Research, 2013Co-Authors: Craig A. Lygate, Liam Sebagmontefiore, Dunja Aksentijevic, Debra J Medway, Dana Dawson, Ten M Hove, Darci Phillips, J De Bono, Imre Hunyor, Keith M ChannonAbstract: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 (>10km/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 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 pre-cursor 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.
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compensation for impaired myocardial phosphotransfer in Guanidinoacetate n methyltransferase knockout mice
Heart, 2010Co-Authors: Dunja Aksentijevic, Liam Sebagmontefiore, Debra J Medway, K Makinen, Craig A. Lygate, Stefan NeubauerAbstract:Guanidinoacetate-N-Methyltransferase (GAMT) is a key enzyme in creatine biosynthesis, such that GAMT knockout mice lack phosphocreatine (PCr) as a substrate for energy transfer via the creatine kinase (CK) reaction. Despite undetectable levels of PCr and creatine, GAMT knockout mice exhibit only minor changes in baseline function and impaired contractile reserve, …
