Cardiac-specific VLCAD deficiency induces dilated cardiomyopathy and cold intolerance

Dingding Xiong, Huamei He, Jeanne James, Chonan Tokunaga, Corey Powers, Yan Huang, Hanna Osinska, Jeffrey Towbin, Enkhsaikhan Purevjav, James A. Balschi, Sabzali Javadov, Francis X. McGowan, Arnold W. Strauss, Zaza Khuchua

Research output: Contribution to journalArticle

19 Citations (Scopus)

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.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume306
Issue number3
DOIs
StatePublished - Feb 1 2014
Externally publishedYes

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Long-Chain Acyl-CoA Dehydrogenase
Dilated Cardiomyopathy
Cardiomyopathies
Hypothermia
Cardiac Myocytes
Fasting
Phenotype
Bradycardia
Hypoglycemia
Knockout Mice
VLCAD deficiency
Myocardium
Fatty Acids
Adenosine Triphosphate
Enzymes

All Science Journal Classification (ASJC) codes

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Cardiac-specific VLCAD deficiency induces dilated cardiomyopathy and cold intolerance. / Xiong, Dingding; He, Huamei; James, Jeanne; Tokunaga, Chonan; Powers, Corey; Huang, Yan; Osinska, Hanna; Towbin, Jeffrey; Purevjav, Enkhsaikhan; Balschi, James A.; Javadov, Sabzali; McGowan, Francis X.; Strauss, Arnold W.; Khuchua, Zaza.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 306, No. 3, 01.02.2014.

Research output: Contribution to journalArticle

Xiong, D, He, H, James, J, Tokunaga, C, Powers, C, Huang, Y, Osinska, H, Towbin, J, Purevjav, E, Balschi, JA, Javadov, S, McGowan, FX, Strauss, AW & Khuchua, Z 2014, 'Cardiac-specific VLCAD deficiency induces dilated cardiomyopathy and cold intolerance', American Journal of Physiology - Heart and Circulatory Physiology, vol. 306, no. 3. https://doi.org/10.1152/ajpheart.00931.2012
Xiong, Dingding ; He, Huamei ; James, Jeanne ; Tokunaga, Chonan ; Powers, Corey ; Huang, Yan ; Osinska, Hanna ; Towbin, Jeffrey ; Purevjav, Enkhsaikhan ; Balschi, James A. ; Javadov, Sabzali ; McGowan, Francis X. ; Strauss, Arnold W. ; Khuchua, Zaza. / Cardiac-specific VLCAD deficiency induces dilated cardiomyopathy and cold intolerance. In: American Journal of Physiology - Heart and Circulatory Physiology. 2014 ; Vol. 306, No. 3.
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