title: O-GlcNAcylation, novel post-translational modification linking myocardial metabolism and cardiomyocyte circadian clock.
abstract: 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.
authors: Division of Cardiovascular Diseases, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.
authors: David J
authors: DJ
authors: Durgan
authors: Betty M
authors: BM
authors: Pat
authors: Boglarka
authors: B
authors: Laczy
authors: Jerry A
authors: JA
authors: Bradley
authors: Ju-Yun
authors: JY
authors: Tsai
authors: Maximiliano H
authors: MH
authors: Grenett
authors: William F
authors: WF
authors: Ratcliffe
authors: Rachel A
authors: RA
authors: Brewer
authors: Jeevan
authors: J
authors: Nagendran
authors: Carolina
authors: C
authors: Villegas-Montoya
authors: Chenhang
authors: C
authors: Zou
authors: Luyun
authors: L
authors: Zou
authors: Russell L
authors: RL
authors: Johnson
authors: Jason R B
authors: JR
authors: Dyck
authors: Molly S
authors: MS
authors: Bray
authors: Karen L
authors: KL
authors: Gamble
authors: John C
authors: JC
authors: Chatham
authors: Martin E
authors: ME
authors: Young
mesh_terms: D056930:ARNTL Transcription Factors / Q000235:genetics / Q000378:metabolism; D000818:Animals; D057906:Circadian Clocks / Q000502:physiology*; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism*; D006031:Glycosylation; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism*; D056950:Period Circadian Proteins / Q000235:genetics / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000502:physiology*
chemical_list: D056930:ARNTL Transcription Factors; C538961:Bmal1 protein, mouse; D006023:Glycoproteins; D009124:Muscle Proteins; C513312:Per2 protein, mouse; D056950:Period Circadian Proteins