Characterising the cardiac effects of dysregulated propionate metabolism using a mouse model of propionic acidaemia

Thesis

Propionate is a naturally-occurring monocarboxylate short-chain fatty acid in humans derived from the mitochondrial metabolism of multiple substrates. There is evidence for dysregulated propionate metabolism (and hence its accumulation), in common metabolic disorders, such as diabetes and obesity. However, the most extreme accumulation of propionate occurs in the inherited metabolic disease, propionic acidaemia (PA). Despite its rarity, PA is one of the commonest organic acidaemias. PA results from a defect in mitochondrial propionyl-CoA carboxylase, the rate-limiting step to propionate metabolism (as propionyl-CoA), resulting in the accumulation of propionate, and other related metabolites such as propionyl-carnitine and 2-methylcitrate. Interestingly, diastolic dysfunction, cardiomyopathy and arrhythmias account for significant morbidity and mortality in PA patients. However, the underlying mechanisms are yet to be fully elucidated.

The aim of this thesis was to characterise the effects of dysregulated propionate metabolism on the heart. This was primarily addressed by using a mouse model of PA (Pcca-/-A138T), in which the levels of propionate generated in vivo are sufficient to produce a metabolic signature of the human disease, but allows the animal to reach adulthood, thereby facilitating the study of cardiac physiology in vivo and in isolated cells. However, there is little information available on how (or whether) the heart is affected in these animals.

Several readouts were used to characterise the cardiac function in PA animals, at the wholeorgan level (metabolomics, ECG, cine-MRI), and the cellular level (Ca2+ signalling). These investigations revealed a metabolic signature of PA in the heart, early signs of contractile dysfunction in vivo, and dysregulated cardiomyocyte Ca2+ handling. Due to previous evidence for propionate acting as a histone deacetylase (HDAC) inhibitor, as well as it being a substrate for histone propionylation, whole-exome sequencing was performed in PA hearts to characterise changes in gene expression. The majority of differentially expressed genes that were sensitive to propionate could be explained by the canonical mechanism of HDAC inhibition. The most significant gene was upregulation of Pde9a, a well-recognised driver of diastolic dysfunction via reduced cGMP-PKG signalling, which can explain the cardiac phenotype. Importantly, Pde9a is a potentially important therapeutic target in PA that warrants further investigation.

Authors: Park, KC

• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: Propionic acidaemia; Organic anions; Cardiac dysfunction; Epigenetics; Propionate; Excitation-contraction coupling; Organic acidaemia
• Subjects: Cardiovascular science; Medical sciences; Cardiology, Experimental; Physiology; Metabolism, Inborn errors of