C-Myc induced compensated cardiac hypertrophy increases free fatty acid utilization for the citric acid cycle

• Published in: Journal of molecular and cellular cardiology Vol. 55; pp. 156 - 164
• Main Authors: Olson, Aaron K., Ledee, Dolena, Iwamoto, Kate, Kajimoto, Masaki, O'Kelly Priddy, Colleen, Isern, Nancy, Portman, Michael A.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.02.2013
• Subjects: Acetyl Coenzyme A - metabolism; Animals; Cardiac hypertrophy; Cardiomegaly - diagnostic imaging; Cardiomegaly - genetics; Cardiomegaly - metabolism; Cardiovascular; Citric Acid Cycle; Compensated hypertrophy; Disease Models, Animal; Echocardiography; Fatty acid oxidation; Fatty Acids, Nonesterified - metabolism; In Vitro Techniques; Male; Mice; Mice, Transgenic; Oxidation-Reduction; Oxygen Consumption; Proteome; Proto-Oncogene Proteins c-myc - genetics; Proto-Oncogene Proteins c-myc - metabolism; Substrate metabolism; Fatty acid oxidation; Cardiac hypertrophy; Compensated hypertrophy; Substrate metabolism
• ISSN: 0022-2828; 1095-8584; 1095-8584
• DOI: 10.1016/j.yjmcc.2012.07.005

The protooncogene C-Myc (Myc) regulates cardiac hypertrophy. Myc promotes compensated cardiac function, suggesting that the operative mechanisms differ from those leading to heart failure. Myc regulation of substrate metabolism is a reasonable target, as Myc alters metabolism in other tissues. We hypothesize that Myc induced shifts in substrate utilization signal and promote compensated hypertrophy. We used cardiac specific Myc-inducible C57/BL6 male mice between 4–6months old that develop hypertrophy with tamoxifen (tam) injections. Isolated working hearts and 13Carbon (13C)-NMR were used to measure function and fractional contributions (Fc) to the citric acid cycle by using perfusate containing 13C-labeled free fatty acids, acetoacetate, lactate, unlabeled glucose and insulin. Studies were performed at pre-hypertrophy (3-days tam, 3dMyc), established hypertrophy (7-days tam, 7dMyc) or vehicle control (Cont). Non-transgenic siblings (NTG) received 7-days tam or vehicle to assess drug effect. Hypertrophy was assessed by echocardiograms and heart weights. Western blots were performed on key metabolic enzymes. Hypertrophy occurred in 7dMyc only. Cardiac function did not differ between groups. Tam alone did not affect substrate contributions in NTG. Substrate utilization was not significantly altered in 3dMyc versus Cont. The free fatty acid FC was significantly greater in 7dMyc versus Cont with decreased unlabeled Fc, which is predominately exogenous glucose. Free fatty acid flux to the citric acid cycle increased while lactate flux was diminished in 7dMyc compared to Cont. Total protein levels of a panel of key metabolic enzymes were unchanged; however total protein O-GlcNAcylation was increased in 7dMyc. Substrate utilization changes for the citric acid cycle did not precede hypertrophy; therefore they are not the primary signal for cardiac growth in this model. Free fatty acid utilization and oxidation increase at established hypertrophy. Understanding the mechanisms whereby this change maintained compensated function could provide useful information for developing metabolic therapies to treat heart failure. The molecular signaling for this metabolic change may occur through O-GlcNAcylation. This article is part of a Special Issue entitled "Focus on Cardiac Metabolism". ► C-Myc activation affects myocardial substrate utilization for the TCA cycle. ► Fatty acid oxidation increases with established compensated cardiac hypertrophy. ► Substrate oxidation is not altered prior to the development of hypertrophy. ► Myocardial O-GlcNAcylation was increased by c-Myc.