Rev-erb-? regulates atrophy-related genes to control skeletal muscle mass.
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PROVIDER: S-EPMC5662766 | BioStudies |
REPOSITORIES: biostudies
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Project description:Rev-erb? is a ligand-dependent nuclear receptor and a key repressor of the molecular clock transcription network. Accumulating evidence indicate that the circadian clock machinery governs diverse biological processes in skeletal muscle, including muscle growth, repair and mass maintenance. The physiological function of Rev-erb? in myogenic regulation remains largely unknown. Here we show that Rev-erb? exerts cell-autonomous inhibitory effects on proliferation and differentiation of myogenic precursor cells, and these actions concertedly inhibit muscle regeneration in vivo. Mechanistic studies reveal Rev-erb? direct transcriptional control of two major myogenic mechanisms, proliferative pathway and the Wnt signaling cascade. Consistent with this finding, primary myoblasts lacking Rev-erb? display significantly enhanced proliferative growth and myogenic progression. Furthermore, pharmacological activation of Rev-erb? activity attenuates, whereas its inhibition by an antagonist promotes these processes. Notably, upon muscle injury, the loss-of-function of Rev-erb? in vivo augmented satellite cell proliferative expansion and regenerative progression during regeneration. Collectively, our study identifies Rev-erb? as a novel inhibitory regulator of myogenic progenitor cell properties that suppresses postnatal myogenesis. Pharmacological interventions to dampen Rev-erb? activity may have potential utilities to enhance regenerative capacity in muscle diseases.
| S-EPMC6418265 | BioStudies
Project description:OBJECTIVE:The loss of skeletal muscle mass and strength are a central feature of traumatic injury and degenerative myopathies. Unfortunately, pharmacological interventions typically fail to stem the long-term decline in quality of life. Reduced Rev-Erb-mediated gene suppression in cultured C2C12 myoblasts has been shown to stimulate myoblast differentiation. Yet the mechanisms that allow Rev-Erb to pleiotropically inhibit muscle differentiation are not well understood. In this study, we sought to elucidate the role of Rev-Erb in the regulation of muscle differentiation and regeneration in vivo. METHODS:Using Rev-Erb?/? shRNAs, pharmacological ligands, and Rev-Erb? null and heterozygous mice, we probed the mechanism of Rev-Erb?/? regulation of muscle differentiation and muscle regeneration. RESULTS:ChIP seq analysis of Rev-Erb in differentiating myoblasts showed that Rev-Erb? did not transcriptionally regulate muscle differentiation through cognate Rev-Erb/ROR-response elements but through possible interaction with the cell fate regulator NF-Y at CCAAT-motifs. Muscle differentiation is stimulated by Rev-Erb release from CCAAT-motifs at promoter and enhancer elements of a number of myogenesis proteins. Partial loss of Rev-Erb expression in mice heterozygous for Rev-Erb? accelerated muscle repair in vivo whereas Rev-Erb knockout mice showed deficiencies in regenerative repair compared to wild type mice. These phenotypic differences between heterozygous and knockout mice were not apparently dependent on MRF induction in response to injury. Similarly, pharmacological disruption of Rev-Erb suppressive activity in injured muscle accelerated regenerative repair in response to acute injury. CONCLUSIONS:Disrupting Rev-Erb activity in injured muscle accelerates regenerative muscle repair/differentiation through transcriptional de-repression of myogenic programs. Rev-Erb, therefore, may be a potent therapeutic target for a myriad of muscular disorders.
| S-EPMC5485243 | BioStudies
Project description:The nuclear receptor Rev-erb-? modulates hepatic lipid and glucose metabolism, adipogenesis and the inflammatory response in macrophages. We show here that Rev-erb-? is highly expressed in oxidative skeletal muscle and that its deficiency in muscle leads to reduced mitochondrial content and oxidative function, as well as upregulation of autophagy. These cellular effects resulted in both impaired mitochondrial biogenesis and increased clearance of this organelle, leading to compromised exercise capacity. On a molecular level, Rev-erb-? deficiency resulted in deactivation of the Lkb1-Ampk-Sirt1-Ppargc-1? signaling pathway. These effects were recapitulated in isolated fibers and in muscle cells after knockdown of the gene encoding Rev-erb-?, Nr1d1. In complementary experiments, Rev-erb-? overexpression in vitro increased the number of mitochondria and improved respiratory capacity, whereas muscle overexpression or pharmacological activation of Rev-erb-? in vivo increased exercise capacity. This study identifies Rev-erb-? as a pharmacological target that improves muscle oxidative function by modulating gene networks controlling mitochondrial number and function.
| S-EPMC3737409 | BioStudies
Project description:Numerous mutational studies have demonstrated that circadian clock proteins regulate behavior and metabolism. Nr1d1(Rev-erb?) is a key regulator of circadian gene expression and a pleiotropic regulator of skeletal muscle homeostasis and lipid metabolism. Loss of Rev-erb? expression induces muscular atrophy, high adiposity, and metabolic syndrome in mice. Here we show that, unlike knockout mice, Nr1d1 heterozygous mice are not susceptible to muscular atrophy and in fact paradoxically possess larger myofiber diameters and improved neuromuscular function, compared to wildtype mice. Heterozygous mice lacked dyslipidemia, a characteristic of Nr1d1 knockout mice and displayed increased whole-body fatty-acid oxidation during periods of inactivity (light cycle). Heterozygous mice also exhibited higher rates of glucose uptake when fasted, and had elevated basal rates of gluconeogenesis compared to wildtype and knockout littermates. Rev-erb? ablation suppressed glycolysis and fatty acid-oxidation in white-adipose tissue (WAT), whereas partial Rev-erb? loss, curiously stimulated these processes. Our investigations revealed that Rev-erb? dose-dependently regulates glucose metabolism and fatty acid oxidation in WAT and muscle.
| S-EPMC7224546 | BioStudies
Project description:The nuclear receptors REV-ERB? and REV-ERB? have been demonstrated to be core members of the circadian clock and participate in the regulation of a diverse set of metabolic functions. Due to their overlapping tissue expression patterns and gene expression profiles, REV-ERB? is thought to be redundant to REV-ERB?. Recent work has highlighted REV-ERB?'s role in the regulation of skeletal muscle oxidative capacity and mitochondrial biogenesis. Considering the similarity between the REV-ERBs and the hypothesized overlap in function, we sought to determine whether REV-ERB?-deficiency presented with a similar skeletal muscle phenotype as REV-ERB?-deficiency. Ectopic overexpression in C2C12 cells demonstrated that REV-ERB? drives mitochondrial biogenesis and the expression of genes involved in fatty acid oxidation. Intriguingly, knock down of REV-ERB? in C2C12 cultures also resulted in mitochondrial biogenesis and increased expression of genes involved in fatty acid ?-oxidation. To determine whether these effects occurred in vivo, we examined REV-ERB?-deficient mice and observed a similar increase in expression of genes involved in mitochondrial biogenesis and fatty acid ?-oxidation. Consistent with these results, REV-ERB?-deficient mice exhibited an altered metabolic phenotype compared to wild-type littermate controls when measured by indirect calorimetry. This likely compensated for the increased food consumption that occurred, possibly aiding in the maintenance of their weight over time. Since feeding behaviors are a direct circadian output, this study suggests that REV-ERB? may have more subtle effects on circadian behaviors than originally identified. Furthermore, these data implicate REV-ERB? in the control of skeletal muscle metabolism and energy expenditure and suggest that development of REV-ERB? versus REV-ERB? selective ligands may have therapeutic utility in the treatment of metabolic syndrome.
| S-EPMC5933789 | BioStudies
Project description:Synchronizing rhythms of behaviour and metabolic processes is important for cardiovascular health and preventing metabolic diseases. The nuclear receptors REV-ERB-? and REV-ERB-? have an integral role in regulating the expression of core clock proteins driving rhythms in activity and metabolism. Here we describe the identification of potent synthetic REV-ERB agonists with in vivo activity. Administration of synthetic REV-ERB ligands alters circadian behaviour and the circadian pattern of core clock gene expression in the hypothalami of mice. The circadian pattern of expression of an array of metabolic genes in the liver, skeletal muscle and adipose tissue was also altered, resulting in increased energy expenditure. Treatment of diet-induced obese mice with a REV-ERB agonist decreased obesity by reducing fat mass and markedly improving dyslipidaemia and hyperglycaemia. These results indicate that synthetic REV-ERB ligands that pharmacologically target the circadian rhythm may be beneficial in the treatment of sleep disorders as well as metabolic diseases.
| S-EPMC3343186 | BioStudies
Project description:Duchenne muscular dystrophy (DMD) is a debilitating X-linked disorder that is fatal. DMD patients lack the expression of the structural protein dystrophin caused by mutations within the DMD gene. The absence of functional dystrophin protein results in excessive damage from normal muscle use due to the compromised structural integrity of the dystrophin associated glycoprotein complex. As a result, DMD patients exhibit ongoing cycles of muscle destruction and regeneration that promote inflammation, fibrosis, mitochondrial dysfunction, satellite cell (SC) exhaustion and loss of skeletal and cardiac muscle function. The nuclear receptor REV-ERB suppresses myoblast differentiation and recently we have demonstrated that the REV-ERB antagonist, SR8278, stimulates muscle regeneration after acute injury. Therefore, we decided to explore whether the REV-ERB antagonist SR8278 could slow the progression of muscular dystrophy. In mdx mice SR8278 increased lean mass and muscle function, and decreased muscle fibrosis and muscle protein degradation. Interestingly, we also found that SR8278 increased the SC pool through stimulation of Notch and Wnt signaling. These results suggest that REV-ERB is a potent target for the treatment of DMD.
| S-EPMC5719458 | BioStudies
Project description:Brown adipose tissue is a major thermogenic organ that plays a key role in maintenance of body temperature and whole-body energy homeostasis. Rev-erb?, a ligand-dependent nuclear receptor and transcription repressor of the molecular clock, has been implicated in the regulation of adipogenesis. However, whether Rev-erb? participates in brown fat formation is not known. Here we show that Rev-erb? is a key regulator of brown adipose tissue development by promoting brown adipogenesis. Genetic ablation of Rev-erb? in mice severely impairs embryonic and neonatal brown fat formation accompanied by loss of brown identity. This defect is due to a cell-autonomous function of Rev-erb? in brown adipocyte lineage commitment and terminal differentiation, as demonstrated by genetic loss- and gain-of-function studies in mesenchymal precursors and brown preadipocytes. Moreover, pharmacological activation of Rev-erb? activity promotes, whereas its inhibition suppresses brown adipocyte differentiation. Mechanistic investigations reveal that Rev-erb? represses key components of the TGF-? cascade, an inhibitory pathway of brown fat development. Collectively, our findings delineate a novel role of Rev-erb? in driving brown adipocyte development, and provide experimental evidence that pharmacological interventions of Rev-erb? may offer new avenues for the treatment of obesity and related metabolic disorders.
| S-EPMC4462032 | BioStudies
Project description:REV-ERB? (NR1D1) is a circadian clock component that functions as a transcriptional repressor. Due to its role in direct modulation of metabolic genes, REV-ERB? is regarded as an integrator of cell metabolism with circadian clock. Accordingly, REV-ERB? is first proposed as a drug target for treating sleep disorders and metabolic syndromes (e.g., dyslipidaemia, hyperglycaemia and obesity). Recent years of studies uncover a rather broad role of REV-ERB? in pathological conditions including local inflammatory diseases, heart failure and cancers. Moreover, REV-ERB? is involved in regulation of circadian drug metabolism that has implications in chronopharmacology. In the meantime, recent years have witnessed discovery of an array of new REV-ERB? ligands most of which have pharmacological activities in vivo. In this article, we review the regulatory role of REV-ERB? in various types of diseases and discuss the underlying mechanisms. We also describe the newly discovered ligands and the old ones together with their targeting potential. Despite well-established pharmacological effects of REV-ERB? ligands in animals (preclinical studies), no progress has been made regarding their translation to clinical trials. This implies certain challenges associated with drug development of REV-ERB? ligands. In particular, we discuss the potential challenges related to drug safety (or adverse effects) and bioavailability. For new drug development, it is advocated that REV-ERB? should be targeted to treat local diseases and a targeting drug should be locally distributed, avoiding the adverse effects on other tissues.
| S-EPMC7086371 | BioStudies
Project description:The circadian clock acts at the genomic level to coordinate internal behavioural and physiological rhythms via the CLOCK-BMAL1 transcriptional heterodimer. Although the nuclear receptors REV-ERB-? and REV-ERB-? have been proposed to form an accessory feedback loop that contributes to clock function, their precise roles and importance remain unresolved. To establish their regulatory potential, we determined the genome-wide cis-acting targets (cistromes) of both REV-ERB isoforms in murine liver, which revealed shared recognition at over 50% of their total DNA binding sites and extensive overlap with the master circadian regulator BMAL1. Although REV-ERB-? has been shown to regulate Bmal1 expression directly, our cistromic analysis reveals a more profound connection between BMAL1 and the REV-ERB-? and REV-ERB-? genomic regulatory circuits than was previously suspected. Genes within the intersection of the BMAL1, REV-ERB-? and REV-ERB-? cistromes are highly enriched for both clock and metabolic functions. As predicted by the cistromic analysis, dual depletion of Rev-erb-? and Rev-erb-? function by creating double-knockout mice profoundly disrupted circadian expression of core circadian clock and lipid homeostatic gene networks. As a result, double-knockout mice show markedly altered circadian wheel-running behaviour and deregulated lipid metabolism. These data now unite REV-ERB-? and REV-ERB-? with PER, CRY and other components of the principal feedback loop that drives circadian expression and indicate a more integral mechanism for the coordination of circadian rhythm and metabolism.
| S-EPMC3367514 | BioStudies