Key result
Transgenic overexpression of the human creatine transporter in murine cardiac muscle resulted in a 5.7-fold increase in cardiac creatine content while maintaining normal ventricular function and survival.
Why the study?
Does elevated cardiac creatine content alter cardiac function under normal physiological conditions in mice?
Does elevated cardiac creatine content alter cardiac function under normal physiological conditions in mice?
Overexpression of the human creatine transporter in mice leads to supraphysiological cardiac creatine levels with normal cardiac function and lifespan, establishing a viable in vivo model for studying cardiac pathologies.
Answers are grounded in this paper and cite their sources.
Elevated cardiac creatine is tolerated in healthy mice; leaves open its effects in disease models.
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 α-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.
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Santacruz et al. (2013) studied Normal cardiac function. Transgenic overexpression of human creatine transporter (CrT) vs. Age-matched wild-type (WT) mice was evaluated on Cardiac creatine content and ventricular function. Transgenic overexpression of the human creatine transporter in murine cardiac muscle resulted in a 5.7-fold increase in cardiac creatine content while maintaining normal ventricular function and survival.
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