Details

Autor(en) / Beteiligte

• Durgan, David J.
• Pat, Betty M.
• Laczy, Boglarka
• Bradley, Jerry A.
• Tsai, Ju-Yun
• Grenett, Maximiliano H.
• Ratcliffe, William F.
• Brewer, Rachel A.
• Nagendran, Jeevan
• Villegas-Montoya, Carolina
• Zou, Chenhang
• Zou, Luyun
• Johnson, Russell L.
• Dyck, Jason R.B.
• Bray, Molly S.
• Gamble, Karen L.
• Chatham, John C.
• Young, Martin E.

Titel

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

Ist Teil von

• The Journal of biological chemistry, 2011-12, Vol.286 (52), p.44606-44619

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2011

Quelle

Free E-Journal (出版社公開部分のみ）

Beschreibungen/Notizen

• 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.