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

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 andmore » 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.« less
Authors:
 [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)
Publication Date:
OSTI Identifier:
1229960
Report Number(s):
PNNL-SA--106577
Journal ID: ISSN 1932-6203; 48162; 600306000
Grant/Contract Number:
AC05-76RL01830
Type:
Accepted Manuscript
Journal Name:
PLoS ONE
Additional Journal Information:
Journal Volume: 10; Journal Issue: 8; Journal ID: ISSN 1932-6203
Publisher:
Public Library of Science
Research Org:
Pacific Northwest National Laboratory (PNNL), Richland, WA (United States)
Sponsoring Org:
USDOE Office of Science (SC), Biological and Environmental Research (BER) (SC-23)
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES Environmental Molecular Sciences Laboratory; heart; fatty acids; glucose metabolism; citric acid cycle; glucose; protein metabolism; enzyme metabolism; oxidation