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

Abstract

UNLABELLED:

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.

• Authors: Dunja Aksentijević, Debra J McAndrew, Anja Karlstädt, Sevasti Zervou, Liam Sebag-Montefiore, Rebecca Cross, Gillian Douglas, Vera Regitz-Zagrosek, Gary D Lopaschuk, Stefan Neubauer, Craig A Lygate
• Journal: Journal of molecular and cellular cardiology (J Mol Cell Cardiol) Vol. 75 Pg. 76-87 (Oct 2014) ISSN: 1095-8584 [Electronic] England
• PMID: 25066696 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014. Published by Elsevier Ltd.

Chemical References

• Carboxy-Lyases
• malonyl-CoA decarboxylase

Topics

• 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, pathology)
• Phenotype
• Substrate Specificity
• Survival Analysis
• Weaning