Submitted on December 18, 2007
Revised on April 28, 2008
Accepted on April 28, 2008
Reduced Heart Size and Increased Myocardial Fuel Substrate Oxidation in ACC2 Mutant Mice
M. Faadiel Essop PhD1, Heidi S. Camp2, Cheol Soo Choi3, Saumya Sharma4, Ryan M. Fryer Ph.D.2, Glenn A. Reinhart2, Patrick H. Guthrie, Assia Bentebibl5, Gerald I. Shulman MD, PhD6, Heinrich Taegtmeyer7, Zeiwei Gu8, Salih J. Wakil8, and Lutfi A. Abu-Elheiga8*
1 Stellenbosch University
2 Abbott Laboratories
3 Yale Medical School
4 University of Texas-Houston Medical School
5 Baylor College of Medicine, University of Barcelona
6 Yale University School of Medicine
7 University of Texas Medical School
8 Baylor College of Medicine
* To whom correspondence should be addressed. E-mail: lutfia{at}bcm.edu.
The cardiac-enriched isoform of acetyl-CoA carboxylase (ACC2) is a key regulator of mitochondrial fatty acid (FA) uptake via carnitine palmitoyltransferase 1 (CPT1). In order to test the hypothesis that oxidative metabolism is upregulated in hearts from animals lacking ACC2 (employing a transgenic Acc2-mutant mouse) we assessed cardiac function in vivo and determined rates of myocardial substrate oxidation ex vivo. When examined by echocardiography there was no difference in systolic function, but left ventricular mass of the Acc2-mutant (MUT) mouse was significantly reduced (~25%) compared to wildtypes (WT). Reduced activation of the mammalian target of rapamycin (mTOR) and its downstream target p70S6K was found in MUT hearts. Exogenous oxidation rates of oleate were increased 22%, and, unexpectedly, exogenous glucose oxidation rates were also increased in MUT hearts. Using a hyperinsulinemic-euglycemic clamp, we found that glucose uptake in MUT hearts was increased by ~83%. Myocardial triglyceride levels were significantly reduced in MUT versus wildtypes while glycogen content was the same. In parallel, transcript levels of PPAR and its target genes, pyruvate dehydrogenase kinase-4 (PDK-4), malonyl-CoA decarboxylase (MCD) and mCPT1 were downregulated in MUT mice. In summary, we report that: 1) Acc2-mutant hearts exhibit a marked preference for the oxidation of both glucose and fatty acids coupled with greater utilization of endogenous fuel substrates (triglycerides); 2) Attenuated mTOR signaling may result in reduced heart sizes observed in Acc2-mutant mice; and 3) Acc2-mutant hearts displayed normal functional parameters despite a significant decrease in size.
