title: Reduced heart size and increased myocardial fuel substrate oxidation in ACC2 mutant mice.
abstract: The cardiac-enriched isoform of acetyl-CoA carboxylase (ACC2) is a key regulator of mitochondrial fatty acid (FA) uptake via carnitine palmitoyltransferase 1 (CPT1). 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 ( approximately 25%) compared with wild-types (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 approximately 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 approximately 83%. Myocardial triglyceride levels were significantly reduced in MUT vs. WT while glycogen content was the same. In parallel, transcript levels of PPARalpha 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 FAs 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.
authors.affiliation: Department of Physiological Sciences, Stellenbosch University, Stellenbosch, South Africa.
authors.forename: M Faadiel
authors.initials: MF
authors.lastname: Essop
authors.forename: Heidi S
authors.initials: HS
authors.lastname: Camp
authors.forename: Cheol Soo
authors.initials: CS
authors.lastname: Choi
authors.forename: Saumya
authors.initials: S
authors.lastname: Sharma
authors.forename: Ryan M
authors.initials: RM
authors.lastname: Fryer
authors.forename: Glenn A
authors.initials: GA
authors.lastname: Reinhart
authors.forename: Patrick H
authors.initials: PH
authors.lastname: Guthrie
authors.forename: Assia
authors.initials: A
authors.lastname: Bentebibel
authors.forename: Zeiwei
authors.initials: Z
authors.lastname: Gu
authors.forename: Gerald I
authors.initials: GI
authors.lastname: Shulman
authors.forename: Heinrich
authors.initials: H
authors.lastname: Taegtmeyer
authors.forename: Salih J
authors.initials: SJ
authors.lastname: Wakil
authors.forename: Lutfi
authors.initials: L
authors.lastname: Abu-Elheiga
mesh_terms: D000103:Acetyl-CoA Carboxylase / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002262:Carboxy-Lyases / Q000235:genetics / Q000378:metabolism; D002334:Carnitine O-Palmitoyltransferase / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation; D004734:Energy Metabolism; D005947:Glucose / Q000378:metabolism; D015309:Glucose Clamp Technique; D006003:Glycogen / Q000378:metabolism; D006352:Heart Ventricles / Q000000981:diagnostic imaging; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D019301:Oleic Acid / Q000378:metabolism; D009929:Organ Size; D010084:Oxidation-Reduction; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases; D013997:Time Factors; D014280:Triglycerides / Q000378:metabolism; D014463:Ultrasonography
chemical_list: D047495:PPAR gamma; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D014280:Triglycerides; D019301:Oleic Acid; D006003:Glycogen; D002334:Carnitine O-Palmitoyltransferase; D011494:Protein Kinases; C546843:mTOR protein, mouse; D017346:Protein Serine-Threonine Kinases; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; D002262:Carboxy-Lyases; C021532:malonyl-CoA decarboxylase; C498191:Acacb protein, mouse; D000103:Acetyl-CoA Carboxylase; D005947:Glucose