c-Myc alters substrate utilization and O-GlcNAc protein posttranslational modifications without altering cardiac function during early aortic constriction
- Seattle Children's Research Institute, Seattle, WA (United States)
- Univ. of Washington, Seattle, WA (United States)
- Pacific Northwest National Lab. (PNNL), Richland, WA (United States)
- Seattle Children's Research Institute, Seattle, WA (United States); Univ. of Washington, Seattle, WA (United States)
- Univ. Catholique de Louvain (Belgium)
Pressure overload cardiac hypertrophy alters substrate metabolism. Prior work showed that myocardial inactivation of c-Myc (Myc) attenuated hypertrophy and decreased expression of metabolic genes after aortic constriction. Accordingly, we hypothesize that Myc regulates substrate preferences for the citric acid cycle during pressure overload hypertrophy from transverse aortic constriction (TAC) and that these metabolic changes impact cardiac function and growth. To test this hypothesis, we subjected mice with cardiac specific, inducible Myc inactivation (MycKO-TAC) and non-transgenic littermates (Cont-TAC) to transverse aortic constriction (TAC; n=7/group). A separate group underwent sham surgery (Sham, n=5). 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. Compared to Sham, Cont-TAC had increased free fatty acid fractional contribution with a concurrent decrease in unlabeled (predominately glucose) contribution. The changes in free fatty acid and unlabeled fractional contributions were abrogated by Myc inactivation during TAC (MycKO-TAC). Additionally, protein posttranslational modification by O-GlcNAc was significantly greater in Cont-TAC versus both Sham and MycKO-TAC. Lastly, 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.
- Research Organization:
- Pacific Northwest National Laboratory (PNNL), Richland, WA (United States)
- Sponsoring Organization:
- USDOE Office of Science (SC), Biological and Environmental Research (BER)
- Grant/Contract Number:
- AC05-76RL01830
- OSTI ID:
- 1229960
- Report Number(s):
- PNNL-SA-106577; 48162; 600306000
- Journal Information:
- PLoS ONE, Vol. 10, Issue 8; ISSN 1932-6203
- Publisher:
- Public Library of ScienceCopyright Statement
- Country of Publication:
- United States
- Language:
- English
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