Phosphorylation regulates cullin-based ubiquitination in tumorigenesis

Cullin-RING ligases (CRLs) recognize and interact with substrates for ubiquitination and degradation, and can be targeted for disease treatment when the abnormal expression of substrates involves pathologic processes. Phosphorylation, either of substrates or receptors of CRLs, can alter their interaction. Phosphorylation-dependent ubiquitination and proteasome degradation influence various cellular processes and can contribute to the occurrence of various diseases, most often tumorigenesis. These processes have the potential to be used for tumor intervention through the regulation of the activities of related kinases, along with the regulation of the stability of specific oncoproteins and tumor suppressors. This review describes the mechanisms and biological functions of crosstalk between phosphorylation and ubiquitination, and most importantly its influence on tumorigenesis, to provide new directions and strategies for tumor therapy.

Microglial Exosome miR-7239-3p Promotes Glioma Progression by Regulating Circadian Genes / 神经科学通报·英文版

Glioma-associated microglial cells, a key component of the tumor microenvironment, play an important role in glioma progression. In this study, the mouse glioma cell line GL261 and the mouse microglia cell line BV2 were chosen. First, circadian gene expression in glioma cells co-cultured with either M1 or M2 microglia was assessed and the exosomes of M2-polarized and unpolarized BV-2 microglia were extracted. Subsequently, we labeled the exosomes with PKH67 and treated GL261 cells with them to investigate the exosome distribution. GL261 cell phenotypes and related protein expression were used to explore the role of M2 microglial exosomes in gliomas. Then a specific miR-7239-3p inhibitor was added to verify miR-7239-3p functions. Finally, the mouse subcutaneous tumorigenic model was used to verify the tumorigenic effect of M2 microglial exosomes in vivo. Our results showed that in gliomas co-cultured with M2 microglia, the expression of the BMAL1 protein was decreased (P < 0.01), while the expression of the CLOCK protein was increased (P < 0.05); opposite results were obtained in gliomas co-cultured with M1 microglia. After treatment with M2 microglial exosomes, the apoptosis of GL261 cells decreased (P < 0.001), while the viability, proliferation, and migration of GL261 cells increased. Increased expression of N-cadherin and Vimentin, and decreased E-cadherin expression occurred upon treatment with M2 microglial exosomes. Addition of an miR-7239-3p inhibitor to M2 microglial exosomes reversed these results. In summary, we found that miR-7239-3p in the glioma microenvironment is recruited to glioma cells by exosomes and inhibits Bmal1 expression. M2 microglial exosomes promote the proliferation and migration of gliomas by regulating tumor-related protein expression and reducing apoptosis.

Increased glycogen synthase kinase 3β activity involves in the decreased expression of Bmal1 induced by amyloid-beta protein 31-35 in HT22 cells / 中华神经科杂志

Objective@#To investigate the effect of glycogen synthase kinase 3β (GSK3β) on the decreased expression of Bmal1 induced by amyloid-beta protein 31-35 (Aβ31-35) in HT22 cells.@*Methods@#HT22 mouse hippocampal cells were divided into control group, Aβ31-35 group and LiCl+Aβ31-35 group by random number table method in the present study. Cells were synchronized to G0/G1 phase by 1% serum starvation for 1 hour (circadian time 0 (CT0)). Cell viability was detected by the cell counting kit-8 assay. The mRNA expression of clock gene Bmal1 was examined by real-time PCR at different CT times. The expression of GSK3β and BMAL1 protein was detected by Western blotting.@*Results@#Compared with the control group, Aβ31-35 induced the decreased expression of Bmal1 mRNA; The expression of both Bmal1 mRNA and BMAL1 protein was decreased significantly at CT20 (Bmal1 mRNA: 0.38±0.06 vs 0.83±0.08, t=4.549, P=0.001; BMAL1 protein: 0.67±0.04 vs 1.00±0.04, t=5.943, P<0.001). In the Aβ31-35 group, GSK3β activity was increased and the ratio of phosphorylated GSK3βS9 to GSK3β was decreased compared to the control group (0.66±0.08 vs 1.02±0.14, t=2.217, P=0.025). Aβ31-35 decreased the viability of HT22 cells (71.85%±6.20% in the Aβ31-35 group vs 98.14%±2.68% in the control group, t=3.891, P=0.006), and the GSK3β inhibitor LiCl pretreatment effectively reversed the decline of the viability induced by Aβ31-35 (90.74%±5.74% in the LiCl+Aβ31-35 group vs 71.85%±6.20% in the Aβ31-35 group, t=3.412, P=0.010). LiCl (in the LiCl+Aβ31-35 group) increased the expression of Bmal1 mRNA and BMAL1 protein significantly at CT20 compared with the Aβ31-35 group (Bmal1 mRNA: 0.72±0.05 vs 0.38±0.06, t=4.378, P=0.001; BMAL1 protein: 0.90±0.04 vs 0.67±0.04, t=4.052, P=0.002).@*Conclusion@#Increased GSK3β activity involved in the decreased expression of Bmal1 induced by Aβ31-35 in HT22 cells.

Increased glycogen synthase kinase 3β activity involves in the decreased expression of Bmal1 induced by amyloid-beta protein 31-35 in HT22 cells / 中华神经科杂志

Objective@#To investigate the effect of glycogen synthase kinase 3β (GSK3β) on the decreased expression of Bmal1 induced by amyloid-beta protein 31-35 (Aβ31-35) in HT22 cells.@*Methods@#HT22 mouse hippocampal cells were divided into control group, Aβ31-35 group and LiCl+Aβ 31-35 group by random number table method in the present study. Cells were synchronized to G0/G1 phase by 1% serum starvation for 1 hour (circadian time 0 (CT0)). Cell viability was detected by the cell counting kit-8 assay. The mRNA expression of clock gene Bmal1 was examined by real-time PCR at different CT times. The expression of GSK3β and BMAL1 protein was detected by Western blotting.@*Results@#Compared with the control group, Aβ31-35 induced the decreased expression of Bmal1 mRNA; The expression of both Bmal1 mRNA and BMAL1 protein was decreased significantly at CT20 (Bmal1 mRNA: 0.38±0.06 vs 0.83±0.08, t=4.549, P=0.001; BMAL1 protein: 0.67±0.04 vs 1.00±0.04, t=5.943, P<0.001). In the Aβ31-35 group, GSK3β activity was increased and the ratio of phosphorylated GSK3βS9 to GSK3β was decreased compared to the control group (0.66±0.08 vs 1.02±0.14, t=2.217, P=0.025). Aβ31-35 decreased the viability of HT22 cells (71.85%±6.20% in the Aβ31-35 group vs 98.14%±2.68% in the control group, t=3.891, P=0.006), and the GSK3β inhibitor LiCl pretreatment effectively reversed the decline of the viability induced by Aβ31-35 (90.74%±5.74% in the LiCl+Aβ31-35 group vs 71.85%±6.20% in the Aβ31-35 group, t=3.412, P=0.010). LiCl (in the LiCl+Aβ31-35 group) increased the expression of Bmal1 mRNA and BMAL1 protein significantly at CT20 compared with the Aβ31-35 group (Bmal1 mRNA: 0.72±0.05 vs 0.38±0.06, t=4.378, P=0.001; BMAL1 protein: 0.90±0.04 vs 0.67±0.04, t=4.052, P=0.002).@*Conclusion@#Increased GSK3β activity involved in the decreased expression of Bmal1 induced by Aβ31-35 in HT22 cells.

BMAL1 regulates mitochondrial fission and mitophagy through mitochondrial protein BNIP3 and is critical in the development of dilated cardiomyopathy

Dysregulation of circadian rhythms associates with cardiovascular disorders. It is known that deletion of the core circadian gene Bmal1 in mice causes dilated cardiomyopathy. However, the biological rhythm regulation system in mouse is very different from that of humans. Whether BMAL1 plays a role in regulating human heart function remains unclear. Here we generated a BMAL1 knockout human embryonic stem cell (hESC) model and further derived human BMAL1 deficient cardiomyocytes. We show that BMAL1 deficient hESC-derived cardiomyocytes exhibited typical phenotypes of dilated cardiomyopathy including attenuated contractility, calcium dysregulation, and disorganized myofilaments. In addition, mitochondrial fission and mitophagy were suppressed in BMAL1 deficient hESC-cardiomyocytes, which resulted in significantly attenuated mitochondrial oxidative phosphorylation and compromised cardiomyocyte function. We also found that BMAL1 binds to the E-box element in the promoter region of BNIP3 gene and specifically controls BNIP3 protein expression. BMAL1 knockout directly reduced BNIP3 protein level, causing compromised mitophagy and mitochondria dysfunction and thereby leading to compromised cardiomyocyte function. Our data indicated that the core circadian gene BMAL1 is critical for normal mitochondria activities and cardiac function. Circadian rhythm disruption may directly link to compromised heart function and dilated cardiomyopathy in humans.

BMAL1 regulates mitochondrial fission and mitophagy through mitochondrial protein BNIP3 and is critical in the development of dilated cardiomyopathy

Dysregulation of circadian rhythms associates with cardiovascular disorders. It is known that deletion of the core circadian gene Bmal1 in mice causes dilated cardiomyopathy. However, the biological rhythm regulation system in mouse is very different from that of humans. Whether BMAL1 plays a role in regulating human heart function remains unclear. Here we generated a BMAL1 knockout human embryonic stem cell (hESC) model and further derived human BMAL1 deficient cardiomyocytes. We show that BMAL1 deficient hESC-derived cardiomyocytes exhibited typical phenotypes of dilated cardiomyopathy including attenuated contractility, calcium dysregulation, and disorganized myofilaments. In addition, mitochondrial fission and mitophagy were suppressed in BMAL1 deficient hESC-cardiomyocytes, which resulted in significantly attenuated mitochondrial oxidative phosphorylation and compromised cardiomyocyte function. We also found that BMAL1 binds to the E-box element in the promoter region of BNIP3 gene and specifically controls BNIP3 protein expression. BMAL1 knockout directly reduced BNIP3 protein level, causing compromised mitophagy and mitochondria dysfunction and thereby leading to compromised cardiomyocyte function. Our data indicated that the core circadian gene BMAL1 is critical for normal mitochondria activities and cardiac function. Circadian rhythm disruption may directly link to compromised heart function and dilated cardiomyopathy in humans.

BMAL1 regulates mitochondrial fission and mitophagy through mitochondrial protein BNIP3 and is critical in the development of dilated cardiomyopathy

Dysregulation of circadian rhythms associates with cardiovascular disorders. It is known that deletion of the core circadian gene Bmal1 in mice causes dilated cardiomyopathy. However, the biological rhythm regulation system in mouse is very different from that of humans. Whether BMAL1 plays a role in regulating human heart function remains unclear. Here we generated a BMAL1 knockout human embryonic stem cell (hESC) model and further derived human BMAL1 deficient cardiomyocytes. We show that BMAL1 deficient hESC-derived cardiomyocytes exhibited typical phenotypes of dilated cardiomyopathy including attenuated contractility, calcium dysregulation, and disorganized myofilaments. In addition, mitochondrial fission and mitophagy were suppressed in BMAL1 deficient hESC-cardiomyocytes, which resulted in significantly attenuated mitochondrial oxidative phosphorylation and compromised cardiomyocyte function. We also found that BMAL1 binds to the E-box element in the promoter region of BNIP3 gene and specifically controls BNIP3 protein expression. BMAL1 knockout directly reduced BNIP3 protein level, causing compromised mitophagy and mitochondria dysfunction and thereby leading to compromised cardiomyocyte function. Our data indicated that the core circadian gene BMAL1 is critical for normal mitochondria activities and cardiac function. Circadian rhythm disruption may directly link to compromised heart function and dilated cardiomyopathy in humans.

Increased glycogen synthase kinase 3β activity involves in the decreased expression of Bmal1 induced by amyloid-beta protein 31-35 in HT22 cells / 中华神经科杂志

Objective To investigate the effect of glycogen synthase kinase 3β (GSK3β) on the decreased expression of Bmal1 induced by amyloid-beta protein 31-35 (Aβ31-35) in HT22 cells.Methods HT22 mouse hippocampal cells were divided into control group,Aβ31-35 group and LiCl+Aβ 31-35 group by random number table method in the present study.Cells were synchronized to G0/G1 phase by 1％ serum starvation for 1 hour (circadian time 0 (CT0)).Cell viability was detected by the cell counting kit-8 assay.The mRNA expression of clock gene Bmal1 was examined by real-time PCR at different CT times.The expression of GSK3β and BMAL1 protein was detected by Western blotting.Results Compared with the control group,Aβ31-35 induced the decreased expression of Bmal1 mRNA;The expression of both Bmal1 mRNA and BMAL1 protein was decreased significantly at CT20 (Bmal1 mRNA:0.38±0.06 vs 0.83±0.08,t=4.549,P=0.001;BMAL1 protein:0.67±0.04 vs 1.00±0.04,t=5.943,P＜0.001).In the Aβ31-35group,GSK3β activity was increased and the ratio of phosphorylated GSK3βS9 to GSK3β was decreased compared to the control group (0.66±0.08 vs 1.02±0.14,t=2.217,P=0.025).Aβ31-35 decreased the viability of HT22 cells (71.85％±6.20％ in the Aβ31-35 group vs 98.14％±2.68％ in the control group,t=3.891,P=0.006),and the GSK3β inhibitor LiC1 pretreatment effectively reversed the decline of the viability induced by Aβ31-35 (90.74％±5.74％ in the LiCl+Aβ31-35 group vs 71.85％±6.20％ in the Aβ31-35 group,t=3.412,P=0.010).LiCl (in the LiCl+Aβ31-35 group) increased the expression of Bmal1 mRNA and BMAL1 protein significantly at CT20 compared with the Aβ31-35 group (Bmal1 mRNA:0.72±0.05 vs 0.38±0.06,t=4.378,P=0.001;BMAL1 protein:0.90±0.04 vs 0.67±0.04,t=4.052,P=0.002).Conclusion Increased GSK3β activity involved in the decreased expression of Bmal 1 induced by Aβ31-35 in HT22 cells.

Effect of Bmal1 expression on radiotherapy sensitivity of nasopharyngeal carcinoma xenograft / 中国肿瘤临床

Objective: To explore the effects of up- and down-regulation of circadian clock gene Bmal1 on the growth and radiation sensitivity of nasopharyngeal carcinoma after CNE1 xenograft in nude mice. Methods: We produced four groups of cells using lentiviral transfection: cells overexpressing CNE1 (CNE1OE), negative control in which there was no overexpression of CNE1 (OENC), cells with short hairpin RNAi (CNE1sh3), and RNAi negative cells (CNE1shNC). We investigated the expression of Bmal1 protein in the aforementioned groups with Western blot. After subcutaneously injecting the four groups of cells in nude mice, the size of the xenograft was measured. Subsequently, the xenografts were irradiated with 15 Gy at 6 MeV, and variation in the xenograft volume was recorded. mRNA and protein expression levels of Bmal1, p53, and p21 in the xenograft were measured with RT-PCR and Western blot, respectively. Results: The CNE1OE group highly expressed Bmal1 protein whereas the CNE1sh3 group was silenced by RNAi as shown with the Western blot, indicating successful transfection. The xenograft in the nude mice developed well. The CNE1OE xenograft volume was lower than that of the CNE1OENC xenograft, whereas the CNE1sh3 xenograft was larger than the CNE1shNC xenograft (P<0.05). CNE1OE, CNE1OENC, and CNE1shNC xenograft volumes shrank after being irradiated (t=4.32, 5.38, 5.16, respectively; P<0.05) and the effect was the highest in the CNE1OE group. However, there was almost no variation in xenograft volume in the CNE1sh3 group. The relative amounts of mRNA and protein of Bmal1, P53, and P21 were higher in the CNE1OE group than in the CNE1OENC group,while they were lower in the CNE1sh3 group compared to the CNE1shNC group (P<0.05). Conclusions: Overexpression of Bmal1 inhibited the growth of the CNE1 xenograft in nude mice and enhanced its radiation sensitivity whereas silencing the Bmal1 gene by RNAi promoted the growth of the xenograft and led to radiation resistance. We believe that Bmal1 overexpression leads to P53 and P21 overexpression, thereby inhibiting the growth of the xenograft.

Effect of Shenghuitang on Bmal1 in Hypothalamus and IL-6 and TNF-α in Hippocampus of APP/PS1 Double Transgenic Dementia Model Mice / 中国实验方剂学杂志

Objective:To investigate the effect of Shenghuitang on learning and memory, biological clock gene[brain and muscle arnt-like 1 (Bmal1)] in hypothalamus and interleukin-6(IL-6)and tumor necrosis factor-α(TNF-α)in hippocampus of APP/PS1 double transgenic dementia model mice, in order to explore the possible mechanism of Shenghuitang to improve learning and memory and sleep disorders. Method:The experimental mice were randomly divided into model group, blank control group, melatonin group, high-dose Shenghuitang group and low-dose Shenghuitang group. Autonomic activity analysis system was used to detect the autonomic activities of mice in each group. Morris water maze was used to detect the learning ability and spatial memory ability of each group. quantitative real-time fluorescence polymerase chain reaction(Real-time PCR) was used to detect the expression of Bmal1 mRNA in the hypothalamic area of mice. Western blot was used to detect the expression of Bmal1 protein in each group. The content of inflammatory factors IL-6 and TNF-α in hippocampus of mice was detected by enzyme-linked immunosorbent assay(ELISA). The correlation between inflammatory factors IL-6, TNF-α and Bmal1 gene was analyzed by pearson analysis. Result:The results of voluntary activities showed that compared with the control group, the number of activities and activity distance of the model group were significantly decreased (PPPPPPPPPPPPPPα in the model group were significantly higher than those in the control group (Pα in the drug group were significantly lower(Pα and Bmal1 were correlated and negatively correlated. Conclusion:Shenghuitang may reduce the levels of inflammatory factors IL-6 and TNF-α in hippocampus by up-regulating the expression of Bmal1 gene in hypothalamic region, thus improving Alzheimer' s disease(AD) and circadian rhythm disorders.

Research progress and new ideas in circadian gene Bmal1 and oncotherapy / 中国肿瘤临床

Circadian rhythm plays a role in regulating life activities and contributes to periodicity, orderliness, and synergy in organ-isms . The Bmal1 gene is one of the core components of the circadian rhythm system; the level of Bmal1 expression differs between tu-mor and normal tissues. Studies have shown that Bmal1 plays different roles in different tumors. Therefore, understanding the role of Bmal1 in different tumorigenesis could provide a new theoretical basis for early detection or effective treatment of tumors. In recent years, with the in-depth studies on time-based approaches, chrono-chemotherapy, which combines pharmacokinetics and biotic rhythm, has become one of the important methods of tumor treatment. Radiotherapy at different times can lead to differences in ra-diosensitivity, which makes chrono-radiotherapy increasingly prominent in tumor treatment. In-depth studies on circadian rhythm in cancer biology could provide new perspectives for tumor treatment.

Role of autophagy in cerebral ischemia-reperfusion injury in diabetic mice: the relationship with HDAC3/Bmal1 signaling pathway / 中华麻醉学杂志

Objective To evaluate the role of autophagy in cerebral ischemia-reperfusion (I/R) injury in diabetic mice and the relationship with histone deacetylase 3 (HDAC3)/Bmal1 signaling pathway.Methods Healthy clean-grade male C57BL/6 mice were used in the study.Diabetes mellitus was induced by intraperitoneal injection of streptozotocin.Thirty-six mice with diabetes mellitus after being fed for 8 weeks were divided into 3 groups (n =12 each) using a random number table method:sham operation group (group S),I/R group and I/R plus HDAC3 inhibitor group (group I/R-H).Cerebral I/R was induced by middle cerebral artery occlusion for 1 h,followed by 24-h reperfusion in anesthetized mice.Specific HDAC3 inhibitor RGFP966 10 mg/kg was subcutaneously injected at 30 min before establishing the model in group I/R-H.Brain tissues were obtained at 24 h of reperfusion for microscopic examination and for determination of cerebral infarct size (by TTC),cell apoptosis (by TUNEL),activities of superoxide dismutase (SOD) and reactive oxygen species (ROS) and malondialdehyde (MDA) content (by colorimetric assay),expression of autophagy-related protein Beclin-1 and LC3B (by immunofluorescence),and expression of HDAC3,Bmal1,GSK-3β and p62 (by Western blot).Apoptosis index (AI) was calculated.Results Compared with group S,the cerebral infarct size was significantly increased,the activities of SOD and ROS and content of MDA in brain tissues were decreased,the expression of Bmal1,p-GSK-3β and HDAC3 was down-regulated,and AI was increased in group I/R (P＜0.05).Compared with group I/ R,the cerebral infarct size was significantly increased,the activities of SOD and ROS and content of MDA in brain tissues were increased,the expression of Bmall,p-GSK-3β,Beclin-1 and LC3B was up-regulated,AI was decreased,and the expression of HDAC3 and p62 was down-regulated in group I/R-H (P＜ 0.05).Conclusion HDAC3/Bmal1 signaling pathway exerts endogenous protective effect through activating autophagy and increasing the antioxidant capacity following cerebral I/R in diabetic mice.

Circadian rhythms in liver metabolism and disease

Mounting research evidence demonstrates a significant negative impact of circadian disruption on human health. Shift work, chronic jet lag and sleep disturbances are associated with increased incidence of metabolic syndrome, and consequently result in obesity, type 2 diabetes and dyslipidemia. Here, these associations are reviewed with respect to liver metabolism and disease.

Effect of Resveratrol, a SIRT1 Activator, on the Interactions of the CLOCK/BMAL1 Complex

BACKGROUND: In mammals, the CLOCK/BMAL1 heterodimer is a key transcription factor complex that drives the cyclic expression of clock-controlled genes involved in various physiological functions and behavioral consequences. Recently, a growing number of studies have reported a molecular link between the circadian clock and metabolism. In the present study, we explored the regulatory effects of SIRTUIN1 (SIRT1), an NAD+-dependent deacetylase, on CLOCK/BMAL1-mediated clock gene expression. METHODS: To investigate the interaction between SIRT1 and CLOCK/BMAL1, we conducted bimolecular fluorescence complementation (BiFC) analyses supplemented with immunocytochemistry assays. BiFC experiments employing deletion-specific mutants of BMAL1 were used to elucidate the specific domains that are necessary for the SIRT1-BMAL1 interaction. Additionally, luciferase reporter assays were used to delineate the effects of SIRT1 on circadian gene expression. RESULTS: BiFC analysis revealed that SIRT1 interacted with both CLOCK and BMAL1 in most cell nuclei. As revealed by BiFC assays using various BMAL1 deletion mutants, the PAS-B domain of BMAL1 was essential for interaction with SIRT1. Activation of SIRT1 with resveratrol did not exert any significant change on the interaction with the CLOCK/BMAL1 complex. However, promoter analysis using Per1-Luc and Ebox-Luc reporters showed that SIRT1 significantly downregulated both promoter activities. This inhibitory effect was intensified by treatment with resveratrol, indicating a role for SIRT1 and its activator in CLOCK/BMAL1-mediated transcription of clock genes. CONCLUSION: These results suggest that SIRT1 may form a regulatory complex with CLOCK/BMAL1 that represses clock gene expression, probably via deacetylase activity.

The expression of melanopsin and clock genes in Xenopus laevis melanophores and their modulation by melatonin

Vertebrates have a central clock and also several peripheral clocks. Light responses might result from the integration of light signals by these clocks. The dermal melanophores of Xenopus laevis have a photoreceptor molecule denominated melanopsin (OPN4x). The mechanisms of the circadian clock involve positive and negative feedback. We hypothesize that these dermal melanophores also present peripheral clock characteristics. Using quantitative PCR, we analyzed the pattern of temporal expression of Opn4x and the clock genes Per1, Per2, Bmal1, and Clock in these cells, subjected to a 14-h light:10-h dark (14L:10D) regime or constant darkness (DD). Also, in view of the physiological role of melatonin in the dermal melanophores of X. laevis, we determined whether melatonin modulates the expression of these clock genes. These genes show a time-dependent expression pattern when these cells are exposed to 14L:10D, which differs from the pattern observed under DD. Cells kept in DD for 5 days exhibited overall increased mRNA expression for Opn4x and Clock, and a lower expression for Per1, Per2, and Bmal1. When the cells were kept in DD for 5 days and treated with melatonin for 1 h, 24 h before extraction, the mRNA levels tended to decrease for Opn4x and Clock, did not change for Bmal1, and increased for Per1 and Per2 at different Zeitgeber times (ZT). Although these data are limited to one-day data collection, and therefore preliminary, we suggest that the dermal melanophores of X. laevis might have some characteristics of a peripheral clock, and that melatonin modulates, to a certain extent, melanopsin and clock gene expression.

THE CIRCADIAN CLOCK AND SKELETAL MUSCLE FUNCTION / 体力科学

Circadian rhythms are approximate 24-hour biological cycles that synchronize the timing of an organism's behavior and physiology to daily environmental changes. This endogenously generated temporal coordination has been experimentally shown to provide an adaptive advantage by enhancing an organism's ability to anticipate daily changes in light, temperature and humidity etc. The molecular mechanism responsible for generating circadian rhythms is a highly conserved gene regulatory network composed of transcriptional-translational feedback loops referred to as the Core-Clock. In mammals, the proteins encoded by Core-Clock genes, Bmal1 and Clock, dimerize to drive transcription of Period and Cryptochrome and the protein products of these genes down-regulate BMAL1 and CLOCK function. BMAL1:CLOCK heterodimers also transcriptionally regulate a group of genes referred to as clock-controlled genes which are believed to be necessary for maintenance of normal cell physiology.In this review, the bases of the circadian rhythms regulation in the central/peripheral tissues are discussed. Particular emphasis has been placed on understanding of circadian regulation of skeletal muscle structure and function. Recently, tissue-specific circadian transcriptome including MyoD1, which is the well-known myogenic lineage regulator, were identified in skeletal muscle. Understanding the molecular, physiological and biophysical mechanisms through which the Core-Clock genes and the tissue-specific circadian transcriptome maintain skeletal muscle structure/function is of great significance with broad translational implications associated with chronic disease, metabolic failure and disuse.