title: Cardiac-specific VLCAD deficiency induces dilated cardiomyopathy and cold intolerance.
abstract: 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.
authors.affiliation: Heart Institute of Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Dingding
authors.initials: D
authors.lastname: Xiong
authors.forename: Huamei
authors.initials: H
authors.lastname: He
authors.forename: Jeanne
authors.initials: J
authors.lastname: James
authors.forename: Chonan
authors.initials: C
authors.lastname: Tokunaga
authors.forename: Corey
authors.initials: C
authors.lastname: Powers
authors.forename: Yan
authors.initials: Y
authors.lastname: Huang
authors.forename: Hanna
authors.initials: H
authors.lastname: Osinska
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Towbin
authors.forename: Enkhsaikhan
authors.initials: E
authors.lastname: Purevjav
authors.forename: James A
authors.initials: JA
authors.lastname: Balschi
authors.forename: Sabzali
authors.initials: S
authors.lastname: Javadov
authors.forename: Francis X
authors.initials: FX
authors.lastname: McGowan
authors.forename: Arnold W
authors.initials: AW
authors.lastname: Strauss
authors.forename: Zaza
authors.initials: Z
authors.lastname: Khuchua
mesh_terms: D044942:Acyl-CoA Dehydrogenase, Long-Chain / Q000172:deficiency*; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002311:Cardiomyopathy, Dilated / Q000201:enzymology* / Q000209:etiology / Q000378:metabolism; D003080:Cold Temperature; D000080984:Congenital Bone Marrow Failure Syndromes; D004195:Disease Models, Animal; D007035:Hypothermia / Q000201:enzymology* / Q000209:etiology / Q000378:metabolism; D008052:Lipid Metabolism, Inborn Errors; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D028361:Mitochondrial Diseases; D009135:Muscular Diseases; D010084:Oxidation-Reduction; D013312:Stress, Physiological
chemical_list: D000255:Adenosine Triphosphate; D044942:Acyl-CoA Dehydrogenase, Long-Chain
keywords: VLCAD; cardiac metabolism; cardiomyopathy; cold intolerance; fatty acid oxidation; mitochondria; mouse