The circadian oscillator in eukaryotes consists of several interlocking feedback loops through which the expression of clock genes is controlled. It is generally assumed that all plant cells contain essentially identical and cell-autonomous multiloop clocks. Here, we show that the circadian clock in the roots of mature Arabidopsis plants differs markedly from that in the shoots and that the root clock is synchronized by a photosynthesis-related signal from the shoot. Two of the feedback loops of the plant circadian clock are disengaged in roots, because two key clock components, the transcription factors CCA1 and LHY, are able to inhibit gene expression in shoots but not in roots. Thus, the plant clock is organ-specific but not organ-autonomous.
Although the major body of research to date has been focused on the role of Bmal1 as a clock transcription activator, cytosolic Bmal1 was recently identified as a factor facilitating protein translation that links the circadian network and the mTOR (Mechanistic Target of Rapamycin) signaling pathway38. Most intriguingly, the Bmal1-mediated mTOR circadian modulation of translation activities is controlled by daily oscillatory magnesium levels in cells39. These recent findings raise the possibility that Bmal1 and the clock could directly participate in muscle hypertrophic pathwaysvia post-transcriptional mechanisms. mTOR signaling, activated by upstream growth factors and PI3 kinase-Akt phosphorylation, is a major regulatory mechanism that promotes protein synthesis to induce skeletal muscle hypertrophy26,40. In addition, PI3K-Akt-mTOR signaling suppresses muscle atrophy40,41. Interestingly, multiple components of the Akt/mTOR signaling pathway are reported to be under circadian regulation. Circadian patterns of expression were detected for Akt1 and ribosomal protein S6 of the hypertrophic signaling, and MuRF1 and Fbxo32 within the atrophic pathway in skeletal muscle28. Notably, the circadian profile of Akt1 phosphorylation, an indicator ofin vivo activity, persists at fasting despite lower levels than ad-libitum feeding, indicating an endogenous rhythm independent of food signals. However, as feeding cycle is dominant zeitgeber for peripheral clocks such as the muscle, there are strong interplays between circadian oscillatory patterns and feeding-fasting switch.
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The skeletal muscle phenotypes found in genetic models of additional clock genes further support the notion that the molecular clock as a regulatory circuit exerts profound influence on skeletal muscle mass and function. Both the clock repressor, Rev-erbα, and its reciprocal transcription activator RORα on the RORE responsive element have been implicated in the regulation of myogenic differentiation42,43. Whereas the constitutive expression of dominant negative Rev-erbα promotes myogenic progression42,44, myogenic differentiation and myogenic pathways gene expression are suppressed by muscle-specific expression of a truncated RORα mutant43. Importantly, the loss of Rev-erbα deficient mice was found to display lower body weight and altered myosin heavy chain (MyHC) isoform expression with a fast-to-slow MyHC isoform transformation in skeletal muscle, suggesting its involvement in muscle mass maintenance and metabolic control45. The findings of opposing actions of Rev-erbα vs. RORα on myogenic pathways, as well as the opposite effects of clock repressor Rev-erbα vs. activator Bmal1 on myogenesis, strongly suggest orchestration of circadian clock gene functions in regulation of myogenic precursor development. Currently, the molecular mechanisms mediating Rev-erbα vs. RORα actions on myogenesis has not been addressed. Furthermore, based on the significantly increased muscle mass demonstrated in the mPer2-null mice, a potential negative effect of the Bmal1/CLOCK inhibitory regulator, Period 2 (Per2), on muscle growth has been suggested21. Per2 functions in the myogenic cascade remain to be seen. Surprisingly, mPer2 and mPer1 functions in the skeletal muscle are distinct, as the altered muscle mass and metabolic pathways are only evident in the mPer2-null mice but not mPer1-deficient animals. Another transcription inhibitor of CLOCK/Bmal1 function, the basic helix-loop-helix factor Dec2/Sharp1, can suppress myogenic differentiation through its inhibitory interaction with MyoD46,47.
The role of the endogenous skeletal muscle molecular clock in regulating muscle metabolic functions and whole body metabolic homeostasis has emerged recently17,69,70. Initial studies of differentially-regulated genes in CLOCK mutants studies indicate that a remarkable 35% percentage of rhythmic genes in muscle are involved in metabolism17. Further, analysis of circadian metabolic genes revealed a temporal separation of genes involved in substrate utilization vs. storage over a daily period, suggesting a clock-controlled orchestration of distinct catabolic and anabolic metabolic pathways in skeletal muscle70.
To address the contribution of skeletal muscle to whole body circadian energy homeostasis, skeletal muscle-specific Bmal1 deletion was created to test the function of Bmal1 in skeletal muscle glucose metabolism69,70. Muscle-specific deletions of Bmal1, either constitutively or through inducible-Cre lines, cause impaired insulin-dependent glucose uptake and reduced glucose oxidation in skeletal muscle69. While canonical insulin signaling pathway is not affected, the level of GLUT4 glucose transporter responsible for glucose uptake was significantly lower. It is interesting that these defects in glucose utilization do not lead to overt changes in insulin sensitivity, possibly due to compensatory mechanisms in other tissues. Applying a global gene expression profiling approach in an inducible mouse model of Bmal1 ablation in muscle, a later study revealed significantly altered expression of genes involved in metabolic substrate oxidation70. Significant down-regulation of circadian genes involved in glucose utilization were observed, along with significant up-regulation of genes involved in lipid metabolism. This gene expression profile suggests muscle fiber type switch to a slow oxidative fiber-type consistent with a substrate shift from carbohydrate to lipid utilization, although the precise fiber type distribution in fast or slow muscle fibers were not assessed70. Thus, two independent studies suggest that the endogenous molecular clock may coordinate skeletal muscle metabolic substrate utilization with metabolite availability occurring during fasting-feeding transitions balance, which could play a significant role in whole-body energy partitioning between tissues to maintain metabolic homeostasis10.
As locomotor activity, the essential function of skeletal muscle in all animal species is under direct circadian clock control through sleep-wake cycles, and the intimate interplay between clock and skeletal muscle physiology is evolutionarily-conserved to ensure fitness and survival.
Accumulating evidence indicates an intimate interplay between circadian clock machinery and metabolic regulations, either at the level of temporal control evident in many key metabolic processes in distinct metabolic tissues, or in the maintenance of whole-body metabolic homeostasis
Abstract:The importance of metabolic health is a major societal concern due to the increasing prevalence of metabolic diseases such as obesity, diabetes, and various cardiovascular diseases. The circadian clock is clearly implicated in the development of these metabolic diseases. Indeed, it regulates physiological processes by hormone modulation, thus helping the body to perform them at the ideal time of day. Since the industrial revolution, the actions and rhythms of everyday life have been modified and are characterized by changes in sleep pattern, work schedules, and eating habits. These modifications have in turn lead to night shift, social jetlag, late-night eating, and meal skipping, a group of customs that causes circadian rhythm disruption and leads to an increase in metabolic risks. Intermittent fasting, especially the time-restricted eating, proposes a solution: restraining the feeding window from 6 to 10 h per day to match it with the circadian clock. This approach seems to improve metabolic health markers and could be a therapeutic solution to fight against metabolic diseases. This review summarizes the importance of matching life habits with circadian rhythms for metabolic health and assesses the advantages and limits of the application of time-restricted fasting with the objective of treating and preventing metabolic diseases.Keywords: time-restricted fasting; intermittent fasting; circadian clock; metabolic diseases; obesity; cardiovascular disease
Sixty-five out- and inpatients with DSM-5 PTSD were assessed by using the Mood Spectrum-Self Report-Lifetime Version (MOODS-SR), a questionnaire for lifetime mood spectrum symptomatology including alterations in circadian/seasonal rhythms and vegetative functions. Six items of the MOODS-SR were combined and dichotomized to assess suicidal ideation and/or attempts.
In the framework of the Spectrum Project (a USA-Italy collaboration), a questionnaire was developed and validated, that explores a full spectrum of lifetime mood spectrum phenomenology (Mood Spectrum-Self Report, MOODS-SR) [35] including dysregulations in rhythmicity and vegetative functions. The MOODS-SR rhythmicity and vegetative functions domain proved to be associated with suicidality in patients with schizophrenia and unipolar, bipolar, borderline personality and panic disorder [36]. Moreover, in a previous study some of us demonstrated that, amongst vegetative functions, dysregulations in sexual functioning and behavior are significantly associated with suicidality in patients with mood disorders [37].
The results of the present study indicate high rates of impaired rhythmicity and vegetative functions, reported across the lifespan, in patients with PTSD. In particular, sleep problems and hypersensitivity to disruptions in circadian and/or seasonal rhythms were the most frequent, with more than half of the patients reporting such symptoms. 2ff7e9595c
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