O-GlcNAcylation, Novel Post-Translational Modification Linking Myocardial Metabolism and Cardiomyocyte Circadian Clock

Nov 10, 2011The Journal of biological chemistry

O-GlcNAcylation, a new molecular change linking heart metabolism and the heart cell’s daily clock

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Abstract

Total cardiac protein O-GlcNAc levels exhibit a diurnal variation in mouse hearts, peaking during the active/awake phase.

The circadian clock regulates multiple myocardial functions, including gene expression and metabolism, in a time-dependent manner.
Genetic removal of the circadian clock in cardiomyocytes eliminates diurnal changes in cardiac O-GlcNAc levels.
Variations in cardiac O-GlcNAc levels are linked to the regulation of specific proteins involved in O-GlcNAcylation and glucose metabolism.
The clock component Bmal1 is identified as a protein modified by O-GlcNAc.
Increasing O-GlcNAcylation leads to reduced levels of Per2 protein and affects the expression of bmal1, influencing the circadian clock's timing.

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The cardiomyocyte circadian clock directly regulates multiple myocardial functions in a time-of-day-dependent manner, including gene expression, metabolism, contractility, and ischemic tolerance. These same biological processes are also directly influenced by modification of proteins by monosaccharides of O-linked β-N-acetylglucosamine (O-GlcNAc). Because the circadian clock and protein O-GlcNAcylation have common regulatory roles in the heart, we hypothesized that a relationship exists between the two. We report that total cardiac protein O-GlcNAc levels exhibit a diurnal variation in mouse hearts, peaking during the active/awake phase. Genetic ablation of the circadian clock specifically in cardiomyocytes in vivo abolishes diurnal variations in cardiac O-GlcNAc levels. These time-of-day-dependent variations appear to be mediated by clock-dependent regulation of O-GlcNAc transferase and O-GlcNAcase protein levels, glucose metabolism/uptake, and glutamine synthesis in an NAD-independent manner. We also identify the clock component Bmal1 as an O-GlcNAc-modified protein. Increasing protein O-GlcNAcylation (through pharmacological inhibition of O-GlcNAcase) results in diminished Per2 protein levels, time-of-day-dependent induction of bmal1 gene expression, and phase advances in the suprachiasmatic nucleus clock. Collectively, these data suggest that the cardiomyocyte circadian clock increases protein O-GlcNAcylation in the heart during the active/awake phase through coordinated regulation of the hexosamine biosynthetic pathway and that protein O-GlcNAcylation in turn influences the timing of the circadian clock.

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O-GlcNAcylation, Novel Post-Translational Modification Linking Myocardial Metabolism and Cardiomyocyte Circadian Clock

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