Metabolic Inflexibility of Malonyl CoA Decarboxylase (MCD) Knockout Mice Leads to Cardiac Remodelling and High Mortality During Peri-Weaning Period

Abstract

MCD inhibition shifts metabolism from fatty acid towards glucose oxidation, which has therapeutic potential for obesity and myocardial ischemic injury. However, ∼40% of patients with MCD deficiency develop cardiomyopathy during infancy. The aim of this study was to clarify the early life link between MCD deficiency, cardiac dysfunction and to identify any underlying systemic and cardiac metabolic perturbations. MCD knockout mice (-/-) obtained by heterozygous breeding exhibited non-Mendelian genotype ratios (31% fewer MCD-/-) with deaths clustered prior to weaning at 21 days. Further deaths occurred, such that only n=10 MCD-/- survived >50 days after which no further increased mortality was observed. Immediately prior to weaning (18 days) MCD-/- mice had lower body weights (P<0.01), elevated body fat (P<0.01), hepatic steatosis (P<0.01) and glycogen depletion (P<0.01) compared to WT littermates. MCD-/- plasma was hyperketonemic, hyperlipidemic, had 60% lower lactate levels and elevated markers of cellular damage (creatine kinase and lactate dehydrogenase P<0.05). MCD-/- hearts exhibited hypertrophy (heart weight:body weight P<0.001), impaired ejection fraction (P<0.05) and were energetically compromised (32% lower total adenine nucleotide pool P<0.05). However differences between WT and MCD-/- converged with age, suggesting that, in surviving MCD-/- mice, early cardiac dysfunction resolves over time. These observations indicate normalisation of the MCD-/- metabolic phenotype and improved cardiac efficiency when switched from a high-fat diet (representative of suckling) to a low-fat post-weaning diet, independent of any developmental changes. Thus, MCD-/- mice consistently exhibited cardiac dysfunction and severe metabolic perturbations while on maternal milk high-fat, low carbohydrate diet and these gradually resolved post-weaning. This suggests that cardiac insufficiency is a common feature of MCD deficiency but that severity is dependent on composition of dietary substrates.