One Carbon Metabolism Defect In Failing Heart

Aberrant cardiac metabolism has long been hypothesized to contribute to heart failure (HF). However, understanding of cardiac metabolism in HF remains incomplete. To fill this gap, we performed metabolomic and RNA sequencing analysis of 48 non-failing (NF) and 39 dilated cardiomyopathy (DCM) hearts. Among many differences, metabolites from one-carbon metabolism were significantly reduced, especially methionine (Met) and s-adenosylmethionine (SAM), a universal methyl donor of methylation. We probed the mechanism behind decreased Met/SAM in DCM hearts. Studies in neonatal rat ventricular myocytes (NRVMs), and in vivo steady-state infusions with isotope tracing showed that Met was mostly imported, rather than recycled, suggesting a defective Met transport in DCM hearts. We next explored the impact of low SAM. DNA and histone methylation remained unchanged, but creatine level was significantly decreased. So, we tested potential creatine synthesis in the heart that was previously unclear. To our surprise, NRVMs synthesized ~50% of their creatine pool when external supply is low, and synthesis was dependent on SAM availability. In summary, we find that the majority of Met in cardiomyocyte is imported, with rapid turnover. We also find that cardiomyocytes synthesize creatine and increase creatine production under stress. Together, these findings suggest that defective Met import may contribute to low creatine and SAM levels and ultimately HF.