c-Myc Alters Substrate Utilization and O-GlcNAc Protein Posttranslational Modifications without Altering Cardiac Function during Early Aortic Constriction.
Hypertrophic stimuli cause transcription of the proto-oncogene c-Myc (Myc). Prior work showed that myocardial knockout of c-Myc (Myc) attenuated hypertrophy and decreased expression of metabolic genes after aortic constriction. Accordingly, we assessed the interplay between Myc, substrate oxidation and cardiac function during early pressure overload hypertrophy. Mice with cardiac specific, inducible Myc knockout (MycKO-TAC) and non-transgenic littermates (Cont-TAC) were subjected to transverse aortic constriction (TAC; n = 7/group). Additional groups underwent sham surgery (Cont-Sham and MycKO-Sham, n = 5 per group). After two weeks, function was measured in isolated working hearts along with substrate fractional contributions to the citric acid cycle by using perfusate with 13C labeled mixed fatty acids, lactate, ketone bodies and unlabeled glucose and insulin. Cardiac function was similar between groups after TAC although +dP/dT and -dP/dT trended towards improvement in MycKO-TAC versus Cont-TAC. In sham hearts, Myc knockout did not affect cardiac function or substrate preferences for the citric acid cycle. However, Myc knockout altered fractional contributions during TAC. The unlabeled fractional contribution increased in MycKO-TAC versus Cont-TAC, whereas ketone and free fatty acid fractional contributions decreased. Additionally, protein posttranslational modifications by O-GlcNAc were significantly greater in Cont-TAC versus both Cont-Sham and MycKO-TAC. In conclusion, Myc alters substrate preferences for the citric acid cycle during early pressure overload hypertrophy without negatively affecting cardiac function. Myc also affects protein posttranslational modifications by O-GlcNAc during hypertrophy, which may regulate Myc-induced metabolic changes.
Seattle Children's Research Institute, Seattle, WA, United States of America.
Dolena
D
Ledee
Department of Pediatrics, Division of Critical Care Medicine, University of Washington, Seattle, Washington, United States of America.
Lincoln
L
Smith
Seattle Children's Research Institute, Seattle, WA, United States of America.
Margaret
M
Bruce
Seattle Children's Research Institute, Seattle, WA, United States of America.
Masaki
M
Kajimoto
Environmental Molecular Sciences Laboratory (EMSL), Pacific Northwest National Laboratory, Richland, WA, United States of America.
Nancy
N
Isern
Seattle Children's Research Institute, Seattle, WA, United States of America; Department of Pediatrics, Division of Cardiology, University of Washington, Seattle, Washington, United States of America.
Michael A
MA
Portman
Seattle Children's Research Institute, Seattle, WA, United States of America; Department of Pediatrics, Division of Cardiology, University of Washington, Seattle, Washington, United States of America.
Aaron K
AK
Olson
D000107:Acetylation; D000117:Acetylglucosamine / Q000378:metabolism; D000818:Animals; D001024:Aortic Valve Stenosis / Q000150:complications / Q000378:metabolism* / Q000503:physiopathology; D002312:Cardiomyopathy, Hypertrophic / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology; D002952:Citric Acid Cycle; D051379:Mice; D011499:Protein Processing, Post-Translational; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*
C489428:Myc protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D000117:Acetylglucosamine