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Guanidinoacetate N-methyltransferase (GAMT) catalyses the final step of creatine biosynthesis such that GAMT−/− mice have undetectable levels of phosphocreatine and creatine and accumulation of the precursor (phospho-)guanidinoacetate (PGA). Like phosphocreatine, PGA acts as an energy reservoir, but energy transfer via creatine kinase is 100 times slower. We hypothesised that reduced energy transfer would be detrimental following myocardial infarction (MI).
GAMT−/− and wild-type controls received coronary artery ligation or sham operation (n=104), with 3D echocardiography and left ventricular haemodynamics after 6 weeks.
Sham GAMT−/− mice had reduced pressure-generating capacity compared with wild-type (wt), with left ventricular systolic pressure and dP/dtmax both significantly lower and impaired contractile reserve. Despite this, there was no significant difference in post-MI survival between GAMT−/− and wt. Both GAMT−/− and wt infarct groups exhibited left ventricular dilatation compared with sham controls, and systolic and diastolic function was also severely impaired. However, there was no significant difference between GAMT−/− and wt infarct groups for left ventricular systolic pressure, left ventricular end-diastolic pressure, dP/dtmax, or Tau, nor for end-diastolic and end-systolic volumes or ejection fraction. Left ventricular/body weight increased by 30% in GAMT−/− and 27% in wt, indicating a similar degree of left ventricular hypertrophy in response to MI.
Loss of energy transfer in GAMT−/− mice was not detrimental to left ventricular remodelling, haemodynamics and survival post-MI. As acute reduction of energy transfer in the rat infarct model dramatically reduces survival, this strongly suggests that significant compensatory processes occur in GAMT−/− mice as a result of creatine loss during early life.
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