Cardiac dysfunction and peri-weaning mortality in malonyl-coenzyme A decarboxylase (MCD) knockout mice as a consequence of restricting substrate plasticity

J Mol Cell Cardiol. 2014 Oct:75:76-87. doi: 10.1016/j.yjmcc.2014.07.008. Epub 2014 Jul 24.

Abstract

Inhibition of malonyl-coenzyme A decarboxylase (MCD) 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 are diagnosed with cardiomyopathy during infancy.

Aim: To clarify the link between MCD deficiency and cardiac dysfunction in early life and to determine the contributing systemic and cardiac metabolic perturbations.

Methods and results: MCD knockout mice ((-/-)) exhibited non-Mendelian genotype ratios (31% fewer MCD(-/-)) with deaths clustered around weaning. Immediately prior to weaning (18days) MCD(-/-) mice had lower body weights, elevated body fat, hepatic steatosis and glycogen depletion compared to wild-type littermates. MCD(-/-) plasma was hyperketonemic, hyperlipidemic, had 60% lower lactate levels and markers of cellular damage were elevated. MCD(-/-) hearts exhibited hypertrophy, impaired ejection fraction and were energetically compromised (32% lower total adenine nucleotide pool). However differences between WT and MCD(-/-) converged with age, suggesting that, in surviving MCD(-/-) mice, early cardiac dysfunction resolves over time. These observations were corroborated by in silico modelling of cardiomyocyte metabolism, which indicated improvement of the MCD(-/-) metabolic phenotype and improved cardiac efficiency when switched from a high-fat diet (representative of suckling) to a standard post-weaning diet, independent of any developmental changes.

Conclusions: MCD(-/-) mice consistently exhibited cardiac dysfunction and severe metabolic perturbations while on a high-fat, low carbohydrate diet of maternal milk and these gradually resolved post-weaning. This suggests that dysfunction is a common feature of MCD deficiency during early development, but that severity is dependent on composition of dietary substrates.

Keywords: Cardiac dysfunction; Fatty acids; Heart failure; Metabolism.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / pathology
  • Animals
  • Carboxy-Lyases / deficiency*
  • Computer Simulation
  • Diet, High-Fat
  • Female
  • Gene Deletion
  • Genotype
  • Heart / physiopathology*
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Myocardium / metabolism
  • Myocardium / pathology
  • Phenotype
  • Substrate Specificity
  • Survival Analysis
  • Weaning*

Substances

  • Carboxy-Lyases
  • malonyl-CoA decarboxylase