title: Cardiac dysfunction and peri-weaning mortality in malonyl-coenzyme A decarboxylase (MCD) knockout mice as a consequence of restricting substrate plasticity.
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.
  
  
  OBJECTIVE
  To clarify the link between MCD deficiency and cardiac dysfunction in early life and to determine the contributing systemic and cardiac metabolic perturbations.
  
  
  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: Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, UK; British Heart Foundation Centre for Research Excellence, University of Oxford, UK.
authors: Dunja
authors: D
authors: Aksentijević
authors: Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, UK; British Heart Foundation Centre for Research Excellence, University of Oxford, UK.
authors: Debra J
authors: DJ
authors: McAndrew
authors: Institute of Gender in Medicine, Charité-Universitätsmedizin Berlin, Berlin, Germany; Center for Cardiovascular Research, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors: Anja
authors: A
authors: Karlstädt
authors: Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, UK; British Heart Foundation Centre for Research Excellence, University of Oxford, UK.
authors: Sevasti
authors: S
authors: Zervou
authors: Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, UK; British Heart Foundation Centre for Research Excellence, University of Oxford, UK.
authors: Liam
authors: L
authors: Sebag-Montefiore
authors: Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, UK; British Heart Foundation Centre for Research Excellence, University of Oxford, UK.
authors: Rebecca
authors: R
authors: Cross
authors: Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, UK; British Heart Foundation Centre for Research Excellence, University of Oxford, UK.
authors: Gillian
authors: G
authors: Douglas
authors: Institute of Gender in Medicine, Charité-Universitätsmedizin Berlin, Berlin, Germany; Center for Cardiovascular Research, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors: Vera
authors: V
authors: Regitz-Zagrosek
authors: Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada.
authors: Gary D
authors: GD
authors: Lopaschuk
authors: Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, UK; British Heart Foundation Centre for Research Excellence, University of Oxford, UK.
authors: Stefan
authors: S
authors: Neubauer
authors: Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, UK; British Heart Foundation Centre for Research Excellence, University of Oxford, UK. Electronic address: clygate@well.ox.ac.uk.
authors: Craig A
authors: CA
authors: Lygate
mesh_terms: D000375:Aging / Q000473:pathology; D000818:Animals; D002262:Carboxy-Lyases / Q000172:deficiency*; D003198:Computer Simulation; D059305:Diet, High-Fat; D005260:Female; D017353:Gene Deletion; D005838:Genotype; D006321:Heart / Q000503:physiopathology*; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D013379:Substrate Specificity; D016019:Survival Analysis; D014886:Weaning
chemical_list: D002262:Carboxy-Lyases; C021532:malonyl-CoA decarboxylase
keywords: Cardiac dysfunction; Fatty acids; Heart failure; Metabolism