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c-Myc alters substrate utilization and O-GlcNAc protein posttranslational modifications without altering cardiac function during early aortic constriction

Journal Article · · PLoS ONE
 [1];  [2];  [1];  [1];  [3];  [4];  [4];  [5]
  1. Seattle Children's Research Institute, Seattle, WA (United States)
  2. Univ. of Washington, Seattle, WA (United States)
  3. Pacific Northwest National Lab. (PNNL), Richland, WA (United States)
  4. Seattle Children's Research Institute, Seattle, WA (United States); Univ. of Washington, Seattle, WA (United States)
  5. Univ. Catholique de Louvain (Belgium)
+ Show Author Affiliations
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) (SC-23)
Grant/Contract Number:
AC05-76RL01830
OSTI ID:
1229960
Report Number(s):
PNNL-SA--106577; 48162; 600306000
Journal Information:
PLoS ONE, Journal Name: PLoS ONE Journal Issue: 8 Vol. 10; ISSN 1932-6203
Publisher:
Public Library of ScienceCopyright Statement
Country of Publication:
United States
Language:
English

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Cited By (5)

AMPK activation counteracts cardiac hypertrophy by reducing O-GlcNAcylation journal January 2018
The role of post‐translational modifications in cardiac hypertrophy journal April 2019
O‐GlcNAc Transferase Promotes Compensated Cardiac Function and Protein Kinase A O‐GlcNAcylation During Early and Established Pathological Hypertrophy From Pressure Overload journal June 2019
Glucose Metabolism in Cardiac Hypertrophy and Heart Failure journal June 2019
O-GlcNAcylation and cardiovascular disease journal April 2017

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Related Subjects

59 BASIC BIOLOGICAL SCIENCES
Environmental Molecular Sciences Laboratory
citric acid cycle
enzyme metabolism
fatty acids
glucose
glucose metabolism
heart
oxidation
protein metabolism