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

Division of Cardiovascular Diseases, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.
Journal of Biological Chemistry (Impact Factor: 4.57). 11/2011; 286(52):44606-19. DOI: 10.1074/jbc.M111.278903
Source: PubMed


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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    • "In contrast to the whole animal CLOCK and BMAL1 KO models the cardiac-specific animals display normal behavioral and neurohumoral rhythms. Note that systemic glucose metabolism appears to be normal despite clear changes in glycolysis, glycogen synthesis and glucose oxidation rhythms in the KO hearts [104]. "
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    ABSTRACT: The incidence of obesity and type 2 diabetes mellitus (T2DM) has risen to epidemic proportions. The pathophysiology of T2DM is complex and involves insulin resistance, pancreatic β-cell dysfunction and visceral adiposity. It has been known for decades that a disruption of biological rhythms (which happens the most profoundly with shift work) increases the risk of developing obesity and T2DM. Recent evidence from basal studies has further sparked interest in the involvement of daily rhythms (and their disruption) in the development of obesity and T2DM. Most living organisms have molecular clocks in almost every tissue, which govern rhythmicity in many domains of physiology, such as rest/activity rhythms, feeding/fasting rhythms, and hormonal secretion. Here we present the latest research describing the specific role played by the molecular clock mechanism in the control of glucose metabolism and speculate on how disruption of these tissue clocks may lead to the disturbances in glucose homeostasis.
    Molecular Metabolism 07/2014; 3(4). DOI:10.1016/j.molmet.2014.03.002
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    • "This negative feedback loop generates cycles of around 24 h in gene expression (Ripperger and Schibler, 2006; Lowrey and Takahashi, 2011). In addition, posttranslational events such as the control of protein phosphorylation, sumoylation, acetylation, O-GlcNAcylation, degradation, and nuclear entry, contribute critically to the generation of daily oscillations in clock gene products (Cardone et al., 2005; Gallego and Virshup, 2007; Asher et al., 2008; Nakahata et al., 2008; Durgan et al., 2011; Reischl and Kramer, 2011; Kim et al., 2012). Central and peripheral clocks have a similar molecular makeup. "
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    ABSTRACT: The impact of impaired circadian rhythm on health has been widely studied in shift workers and trans-meridian travelers. A part from its correlation with sleep and mood disorders, biological rhythm impairment is a recognized risk factor for cardiovascular diseases and breast cancer. Preeclampsia is a major public health issue, associated with a significant maternal and fetal morbidity and mortality worldwide. While the risks factors for this condition such as obesity, diabetes, pre-existing hypertension have been identified, the underlying mechanism of this multi-factorial disease is yet not fully understood. The disruption of the light/dark cycle in pregnancy has been associated with adverse outcomes. Slightly increased risk for "small for gestational age" babies, "low birth weight" babies, and preterm deliveries has been reported in shift working women. Whether altered circadian cycle represents a risk factor for preeclampsia or preeclampsia is itself linked with an abnormal circadian cycle is less clear. There are only few reports available, showing conflicting results. In this review, we will discuss recent observations concerning circadian pattern of blood pressure in normotensive and hypertensive pregnancies. We explore the hypothesis that circadian misalignments may represent a risk factor for preeclampsia. Unraveling potential link between circadian clock gene and preeclampsia could offer a novel approach to our understanding of this multi-system disease specific to pregnancy.
    Frontiers in Endocrinology 04/2013; 4:47. DOI:10.3389/fendo.2013.00047
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    • "We have previously described that the acrophase of diastolic blood pressure (DBP), i.e. the time of the maximum of the DBP, registered in type 1 diabetes (T1D) patients occurred significantly earlier than normal and DBP ecphasia (altered circadian timing) was more pronounced in patients with lower heart rate (HR) variability during deep breathing [2]. Several mechanisms could be involved in linking diabetes mellitus with changes in circadian rhythms of BP and HR, such as interactions between metabolism and circadian gene network [3,4], suppressed clock gene oscillations in vasculature [5], or insulin-melatonin antagonism [6]. However, phase shift in acrophase of DBP has never been specifically addressed. "
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    ABSTRACT: Background Abnormal circadian blood pressure patterns have been associated with cardiovascular disease in diabetes mellitus. We have described that the acrophase of diastolic blood pressure (DBP) registered in type 1 diabetes (T1D) patients was significantly earlier than normal and DBP ecphasia was more pronounced in patients with lower heart rate variability during deep breathing. The aim of this study was to compare the circadian rhythm characteristics of BP among different groups: normotensive (NT) control subjects, patients affected by T1D and type 2 diabetes (T2D), and patients with essential hypertension (HT). Findings We retrospectively evaluated ambulatory blood pressure monitoring records in 30 NT, 20 T1D, 20 T2D, 20 HT whose fasting plasma glucose and HbA1c were contemporaneously measured. The four groups were well-matched regarding age, gender, and BMI. Systolic blood pressure (SBP) and DBP midline-estimating statistic of rhythm were higher in T1D, T2D, and HT groups. DBP ecphasia was present only in the diabetic individuals: the acrophase of DBP occurred four hours earlier than normal in T1D group, whereas two hours earlier in T2D group. In a multiple regression analysis, only HbA1c and SBP acrophase were statistically significant correlates of DBP acrophase. Conclusions People with diabetes mellitus, both type 1 and type 2, have their circadian acrophase of DBP occurring 2–4 hours earlier than normotensive and hypertensive subjects. Altered circadian timing of DBP, potential trigger of cardiovascular events, seems to be a distinguishing feature of diabetes mellitus and correlates with the previous 2–3 months of glycaemic control.
    Diabetology and Metabolic Syndrome 12/2012; 4(1):51. DOI:10.1186/1758-5996-4-51 · 2.17 Impact Factor
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