Cardiac-specific VLCAD deficiency induces dilated cardiomyopathy and cold intolerance. Am J Physiol Heart Circ Physiol 2014 Feb;306(3):H326-38
Date
11/29/2013Pubmed ID
24285112Pubmed Central ID
PMC3920141DOI
10.1152/ajpheart.00931.2012Scopus ID
2-s2.0-84893407026 (requires institutional sign-in at Scopus site) 36 CitationsAbstract
The very long-chain acyl-CoA dehydrogenase (VLCAD) enzyme catalyzes the first step of mitochondrial β-oxidation. Patients with VLCAD deficiency present with hypoketotic hypoglycemia and cardiomyopathy, which can be exacerbated by fasting and/or cold stress. Global VLCAD knockout mice recapitulate these phenotypes: mice develop cardiomyopathy, and cold exposure leads to rapid hypothermia and death. However, the contribution of different tissues to development of these phenotypes has not been studied. We generated cardiac-specific VLCAD-deficient (cVLCAD(-/-)) mice by Cre-mediated ablation of the VLCAD in cardiomyocytes. By 6 mo of age, cVLCAD(-/-) mice demonstrated increased end-diastolic and end-systolic left ventricular dimensions and decreased fractional shortening. Surprisingly, selective VLCAD gene ablation in cardiomyocytes was sufficient to evoke severe cold intolerance in mice who rapidly developed severe hypothermia, bradycardia, and markedly depressed cardiac function in response to fasting and cold exposure (+5°C). We conclude that cardiac-specific VLCAD deficiency is sufficient to induce cold intolerance and cardiomyopathy and is associated with reduced ATP production. These results provide strong evidence that fatty acid oxidation in myocardium is essential for maintaining normal cardiac function under these stress conditions.
Author List
Xiong D, He H, James J, Tokunaga C, Powers C, Huang Y, Osinska H, Towbin JA, Purevjav E, Balschi JA, Javadov S, McGowan FX Jr, Strauss AW, Khuchua ZMESH terms used to index this publication - Major topics in bold
Acyl-CoA Dehydrogenase, Long-ChainAdenosine Triphosphate
Animals
Cardiomyopathy, Dilated
Cold Temperature
Disease Models, Animal
Hypothermia
Lipid Metabolism, Inborn Errors
Mice
Mice, Inbred C57BL
Mice, Knockout
Mitochondrial Diseases
Muscular Diseases
Oxidation-Reduction
Stress, Physiological
