The Role of BCAT1 on Pediatric Dilated Cardiomyopathy

Abstract

BackgroundPediatric dilated cardiomyopathy (DCM) is a devastating and poorly understood disease with most clinical treatment paradigms extrapolated from the adult population. Our studies showed that aspects of metabolism and mitochondria function are dysregulated in pediatric hearts. One potential factor which may be implicated in pediatric cardiac dysfunction is the Branched‐Chain Amino Acid Transaminase 1 (BCAT1), an enzyme highly expressed in pediatric non‐failing hearts and down‐regulated in response to DCM‐induced heart failure. While BCAT1’s role in cardiac dysfunction is unclear, in cancer cells and macrophages, BCAT1 is important for mitochondria function. The objective of this study is to investigate the role of BCAT1 in the heart, which may result in age‐specific therapies.MethodsWe measured metabolite composition of the pediatric DCM and non‐failing (NF) hearts. Activity and level of BCAT1 by enzymatic assay, RT‐qPCR and Western Blot in adult and pediatric and DCM and NF hearts was also measured. Pathologic changes in gene expression and mitochondrial function were assessed in Neonatal Rat Ventricular Myocytes (NRVMs) by RT‐qPCR and Seahorse assay in the presence or absence of BCAT1 inhibitor.ResultsAnalysis of metabolite content showed a dramatic accumulation of branched‐chain amino acids (BCAAs) in pediatric DCM hearts. BCAT1 mRNA and protein levels are increased in pediatric NF hearts compared to adult NF hearts, and decreased in pediatric DCM hearts. In addition, inhibition of BCAT1 in NRVMs results in pathologic gene expression and inhibition of pro‐inflammatory cytokines. Finally, Seahorse assay showed a decrease of mitochondrial respiration in NRVMs treated with BCAT1 inhibitor.ConclusionsDecreased levels of BCAT1 are detrimental to the pediatric failing heart. These findings suggest that BCAT1 could be a specific therapeutic target for the pediatric population.Support or Funding InformationR01 HL139968 and HL126928