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Numerous mutational studies have demonstrated that circadian clock proteins regulate behavior and metabolism. Nr1d1(Rev-erbα) is a key regulator of circadian gene expression and a pleiotropic regulator of skeletal muscle homeostasis and lipid metabolism. Loss of Rev-erbα 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-erbα ablation suppressed glycolysis and fatty acid-oxidation in white-adipose tissue (WAT), whereas partial Rev-erbα loss, curiously stimulated these processes. Our investigations revealed that Rev-erbα dose-dependently regulates glucose metabolism and fatty acid oxidation in WAT and muscle.

Non-alcoholic fatty liver (NAFLD) over the past years has become a metabolic pandemic linked to a collection of metabolic diseases. The nuclear receptors ERRs, REV-ERBs, RORs, FXR, PPARs, and LXR are master regulators of metabolism and liver physiology. The characterization of these nuclear receptors and their biology has promoted the development of synthetic ligands. The possibility of targeting these receptors to treat NAFLD is promising, as several compounds including Cilofexor, thiazolidinediones, and Saroglitazar are currently undergoing clinical trials. This review focuses on the latest development of the pharmacology of these metabolic nuclear receptors and how they may be utilized to treat NAFLD and subsequent comorbidities.

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.

Numerous mutational studies have demonstrated that circadian clock proteins regulate behavior and metabolism. Nr1d1(Rev-erb[alpha]) is a key regulator of circadian gene expression and a pleiotropic regulator of skeletal muscle homeostasis and lipid metabolism. Loss of Rev-erb[alpha] 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[alpha] ablation suppressed glycolysis and fatty acid-oxidation in white-adipose tissue (WAT), whereas partial Rev-erb[alpha] loss, curiously stimulated these processes. Our investigations revealed that Rev-erb[alpha] dose-dependently regulates glucose metabolism and fatty acid oxidation in WAT and muscle.

A mosaic of cross-phylum chemical interactions occurs between all metazoans and their microbiomes. A number of molecular families that are known to be produced by the microbiome have a marked effect on the balance between health and disease 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 – 9 . Considering the diversity of the human microbiome (which numbers over 40,000 operational taxonomic units 10 ), the effect of the microbiome on the chemistry of an entire animal remains underexplored. Here we use mass spectrometry informatics and data visualization approaches 11 , 12 – 13 to provide an assessment of the effects of the microbiome on the chemistry of an entire mammal by comparing metabolomics data from germ-free and specific-pathogen-free mice. We found that the microbiota affects the chemistry of all organs. This included the amino acid conjugations of host bile acids that were used to produce phenylalanocholic acid, tyrosocholic acid and leucocholic acid, which have not previously been characterized despite extensive research on bile-acid chemistry 14 . These bile-acid conjugates were also found in humans, and were enriched in patients with inflammatory bowel disease or cystic fibrosis. These compounds agonized the farnesoid X receptor in vitro, and mice gavaged with the compounds showed reduced expression of bile-acid synthesis genes in vivo. Further studies are required to confirm whether these compounds have a physiological role in the host, and whether they contribute to gut diseases that are associated with microbiome dysbiosis. Metabolomics data from germ-free and specific-pathogen-free mice reveal effects of the microbiome on host chemistry, identifying conjugations of bile acids that are also enriched in patients with inflammatory bowel disease or cystic fibrosis.

The nuclear receptors NR1D1 (REV-ERB-Alpha) and NR1D2 (REV-ERB-Beta) are transcriptional repressors that are both components of the molecular clock. The circadian clock is a known regulator of skeletal muscle (SkM) mass and repair. REV-ERB is highly expressed in SkM and is known to inhibit myoblast differentiation in vitro. However, it is not clear what is REV-ERB’s role in regulating SkM repair in vivo. Investigation of Rev-erb-Alpha gene dosage in mice revealed a robust difference in SkM size. Reduction of Rev-erb-Alpha produced an increase in SkM hypertrophy, while the complete ablation of Rev-erb-Alpha resulted in SkM degradation, suggesting SkM homeostasis is highly sensitive to Rev-erb-alpha expression. Moreover, examination of Rev-erb-Alpha KO mice revealed chronic fatty acid oxidation in their muscle and, therefore, may explain why they exhibit high levels of SkM catabolism. The reduction of Rev-erb-Alpha expression and pharmacological antagonism (SR8278) of REV-ERB produced an enhancement of muscle differentiation in vitro and in vivo, suggesting REV-ERB may be a suitable target to stimulate muscle repair. Dystrophic mdx mice treated with SR8278 exhibited higher lean mass levels and strength. Further investigation revealed inhibiting REV-ERB with SR8278 modulated a collection of developmental pathways and increased satellite cell renewal. Mechanistic inquiry by chromatin immunoprecipitation followed by deep sequencing in proliferating mouse myoblasts revealed REV-ERB-Alpha regulated a plethora of developmental genes by indirect DNA binding through the transcriptional complex known as Nuclear Factor-Y(NF-Y). We found that REV-ERB-Alpha was released at NF-Y binding sites upon myoblast differentiation, indicating the loss of REV-ERB-Alpha’s interaction with NF-Y is needed to drive myoblast fusion. Upon myoblast differentiation REV-ERB-Alpha began to sequester at RORE-like motifs in differentiating myoblasts, suggesting REV-ERB-Alpha may “switch” motifs to regulate other cellular processes once myoblast development is complete. Lastly, we investigated if synthetic REV-ERB ligands could modulate gene expression of human myoblast undergoing proliferation and differentiation and found that REV-ERB antagonism increased developmental gene expression in human SkM. This implies that REV-ERB antagonism may have utility in enhancing muscle repair in humans.

Numerous mutational studies have demonstrated that circadian clock proteins regulate behavior and metabolism. Nr1d1(Rev-erbα) is a key regulator of circadian gene expression and a pleiotropic regulator of skeletal muscle homeostasis and lipid metabolism. Loss of Rev-erbα 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-erbα ablation suppressed glycolysis and fatty acid-oxidation in white-adipose tissue (WAT), whereas partial Rev-erbα loss, curiously stimulated these processes. Our investigations revealed that Rev-erbα dose-dependently regulates glucose metabolism and fatty acid oxidation in WAT and muscle.

We present SquiggleNet, the first deep-learning model that can classify nanopore reads directly from their electrical signals. SquiggleNet operates faster than DNA passes through the pore, allowing real-time classification and read ejection. Using 1 s of sequencing data, the classifier achieves significantly higher accuracy than base calling followed by sequence alignment. Our approach is also faster and requires an order of magnitude less memory than alignment-based approaches. SquiggleNet distinguished human from bacterial DNA with over 90% accuracy, generalized to unseen bacterial species in a human respiratory meta genome sample, and accurately classified sequences containing human long interspersed repeat elements.