Cardiac phenotype of mitochondrial creatine kinase knockout mice is modified on a pure C57BL/6 genetic background

Lygate, Craig A.; Hunyor, Imre; Medway, Debra J.; Bono, Joseph de; Dawson, Dana; Wallis, Julie; Sebag-Montefiore, Liam; Neubauer, Stefan

doi:10.1016/j.yjmcc.2008.09.710

Cited by 29 publications

(28 citation statements)

References 34 publications

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“…normal total creatine levels but non-functioning CK system. These mice have impaired exercise capacity in voluntary running experiments 37, 38 and eventually develop baseline dysfunction and cardiac hypertrophy 39 in some, but not all studies 38 , dependent on genetic background. 40 This represents a more severe phenotype than creatine-deficiency models, which suggests that loss of substrate and loss of enzyme are not biochemically equivalent.…”

Section: Discussionmentioning

confidence: 99%

Living Without Creatine

Lygate

Dawson

Hove

et al. 2013

Circulation Research

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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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Section: Discussionmentioning

confidence: 99%

Living Without Creatine

Lygate

Dawson

Hove

et al. 2013

Circulation Research

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“…Apart from the construct and exon targeted to disrupt the Fgf-16 gene, the most obvious difference between these two mouse models is their genetic background; chimera were generated using either 129/SvJderived embryonic stem (ES) cells and backcrossing to Black Swiss (Bsw) mice (Lu et al, 2008a) or C57BL/6-derived ES cells backcrossing to C57BL/6 mice (Hotta et al, 2008). The presence of modifier genes in a particular genetic background and their effect on phenotype has been described in other mouse models with gene disruptions (Krezowski et al, 2004;Strunk et al, 2004;Sebastiani et al, 2006;Astrof et al, 2007;Lygate et al, 2009). Clearly, this genetic effect has implications from a systems perspective with regard to more complex and common disorders, including cardiovascular disease.…”

Section: Introductionmentioning

confidence: 99%

“…Breeding into a C57BL/6 background with relatively few (four to eight) back crossings has been linked to phenotypic changes as well as rescue of embryonic lethality in other genetically disrupted mouse models (Hao et al, 2005;Lygate et al, 2009). The observation of a range of (facial and heart) phenotypes in the progeny backcrossed to C57BL/6 mice reported here, as well as the observations made with regard to FGF-8 RNA levels, suggests that there are modifications to expression of multiple genes, not a single gene, likely due to heterogeneity of modifiers.…”

mentioning

confidence: 99%

Embryonic Survival and Severity of Cardiac and Craniofacial Defects Are Affected by Genetic Background in Fibroblast Growth Factor-16 Null Mice

Jin

et al. 2010

DNA and Cell Biology

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Disruption of the X-chromosome fibroblast growth factor 16 (Fgf-16) gene, a member of the FGF-9 subfamily with FGF-20, was linked with an effect on cardiac development in two independent studies. However, poor trabeculation with lethality by embryonic day (E) 11.5 was associated with only one, involving maintenance in Black Swiss (Bsw) versus C57BL/6 mice. The aim of this study was to examine the potential influence of genetic background through breeding the null mutation onto an alternate (C57BL/6) background. After three generations, 25% of Fgf-16(-/Y) mice survived to adulthood, which could be reversed by reducing the contribution of the C57BL/6 genetic background by back crossing to another strain. There was no significant difference between FGF-9 and FGF-20 RNA levels in Fgf-16 null versus wild-type mice regardless of strain. However, FGF-8 RNA levels were reduced significantly in Bsw but not C57BL/6 mice. FGF-8 is linked to anterior heart development and like the FGF-9 subfamily is reportedly expressed at E10.5. Like FGF-16, neuregulin as well as signaling via ErbB2 and ErbB4 receptors have been linked to trabeculae formation and cardiac development around E10.5. Basal neuregulin, ErbB2, and ErbB4 as well as FGF-8, FGF-9, and FGF-16 RNA levels varied in Bsw versus C57BL/6 mice. These data are consistent with the ability of genetic background to modify the phenotype and affect embryonic survival in Fgf-16 null mice.

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“…However, the mitochondrial CK knockout mouse does not develop a cardiac phenotype potentially attributable to compensatory increase in cytosolic CK and an increase in mitochondrial volume. 43 …”

Section: Disturbed Energy Transfermentioning

confidence: 99%