Deciphering One Carbon Metabolism Defect in Heart Failure

PROJECT ABSTRACT 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 low, especially methionine and s-adenosylmethionine (SAM), a universal methyl donor of methylation. In parallel, we also observed significant decrease of creatine, and increase of phosphatidylcholine (PC) in DCM hearts, which both are methylation product of SAM. Creatine is a critical metabolite for cardiac contraction, and PC is the most abundant phospholipids in the membrane. These observations and additional preliminary data have led to the hypothesis that cardiac injury causes membrane remodeling and excessive PC synthesis that drains the SAM pool, suppressing the generation of creatine, and ultimately contributing to cardiac metabolic insufficiency. Therefore, in Aim 1, I will lay groundwork for one-carbon metabolism in the heart by quantitively define cardiac- methionine/SAM flux and dynamics in vitro and in vivo using isotope labeled methionine tracing. In Aim 2, I will test if SAM deficiency can cause or worsen heart failure using cardiac specific SAM depletion mouse model. In Aim 3, I will quantify cardiac creatine synthesis rates and estimate contribution of reduced creatine in HF caused by low SAM levels. In Aim 4, I will test if cardiac remodeling increases PC synthesis and drains the SAM pool. The support from K99/R00 pathway to independence award will provide the applicant with the necessary training in cardiac metabolism to successfully achieve goals of each aim. This training will be guided and supported by a team of world class scientists from University of Pennsylvania, Cincinnati children’s hospital and Princeton University. In conclusion, this project will lay groundwork for one-carbon metabolism in the heart and identify cause and consequences of low SAM in the heart failure, which will be a pioneering discovery that may lead to new options for diagnosis and treatment of heart failure.