Cardiac structure and function during ageing in energetically compromised Guanidinoacetate N-methyltransferase (GAMT)-knockout mice - a one year longitudinal MRI study.
Schneider JE., Stork LA., Bell JT., ten Hove M., Isbrandt D., Clarke K., Watkins H., Lygate CA., Neubauer S.
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 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.