Propionic acidaemia (PA) is an autosomal recessive disorder characterised by malfunctional mitochondrial propionyl-CoA carboxylase. Consequences of this inborn error of metabolism (IEM) is defective catabolism of propiogenic substrates (branched-chain amino acids, odd-number fatty acids, etc.) leading to mitochondrial accumulation of propionyl CoA and its derivatives. Accumulation of propionate derivatives in the cytoplasm and plasma leads to intra- and extracellular metabolic acidosis. The clinical manifestation is severe; arrhythmia and cardiomyopathy (hypertrophic and dilated) are cited as major causes of death. Little is known of the underlying mechanisms. Since butyrate is in the same homologous series as propionate, and is itself a well-established inhibitor of histone deacetylases (HDACs), it is plausible pro-hypertrophic signalling in PA is epigenetically regulated. Therefore, we investigated the effects of propionate on cardiomyocytes.
In preliminary work, culturing neonatal rat ventricular myocytes (NRVMs) in a chemical milieu mimicking PA (6 mM propionate; 200 M ammonium; 18 mM bicarbonate; pH 7.15) increased significantly cardiomyocyte area. Treating adult rat VMs with PA-medium increased significantly histone-3 lysine-9 acetylation, phenocopying the effects of butyrate. To determine the gene expression profile associated with PA, RNA-sequencing was performed on polyadenylated RNA extracted from NRVMs, treated with control-, butyrate-, or PA-medium. In PA-medium, Differentially Expressed Gene analysis demonstrated 3.0% of genes were upregulated and 3.0% downregulated (FDR<0.0001). Gene Ontology Enrichment Analysis using DAVID revealed ‘cardiac muscle contraction’ and ‘metabolic pathways’ as being significantly enriched. 1.9% of genes were upregulated in both PA and butyrate, representing candidates that could be regulated by HDACs. We are currently validating these hits.
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