c-Myc Alters Substrate Utilization and O-GlcNAc Protein Posttranslational Modifications without Altering Cardiac...

Area of Science:

• Cardiovascular Biology
• Molecular Cardiology
• Metabolic Regulation

Background:

• Hypertrophic stimuli induce c-Myc (Myc) transcription in the heart.
• Myocardial c-Myc knockout previously attenuated hypertrophy and altered metabolic gene expression post-aortic constriction.

Purpose of the Study:

• To investigate the interplay between Myc, substrate oxidation, and cardiac function during early pressure overload-induced cardiac hypertrophy.
• To elucidate Myc's role in regulating metabolic substrate utilization and protein modifications in the hypertrophied heart.

Main Methods:

• Cardiac-specific inducible Myc knockout mice (MycKO) underwent transverse aortic constriction (TAC) or sham surgery.
• Cardiac function was assessed using isolated working hearts.
• Substrate fractional contributions to the citric acid cycle were determined using 13C-labeled substrates.
• O-GlcNAc protein posttranslational modifications were analyzed.

Main Results:

• Cardiac function was comparable between MycKO-TAC and control (Cont-TAC) groups, with a trend towards improved contractility (+dP/dT) and relaxation (-dP/dT) in MycKO-TAC.
• Myc knockout altered substrate utilization during TAC, increasing unlabeled substrate contribution while decreasing ketone and free fatty acid contributions.
• O-GlcNAc modifications were significantly elevated in Cont-TAC compared to sham and MycKO-TAC groups.

Conclusions:

• Myc plays a role in modulating substrate preferences for the citric acid cycle during early pressure overload hypertrophy.
• Myc influences O-GlcNAc protein modifications during cardiac hypertrophy, potentially mediating Myc-induced metabolic alterations.
• Targeting Myc may offer therapeutic strategies for managing metabolic changes in cardiac hypertrophy.