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      Rev-erb-α modulates skeletal muscle oxidative capacity by regulating mitochondrial biogenesis and autophagy

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          Abstract

          The nuclear receptor Rev-erb-α modulates hepatic lipid and glucose metabolism, adipogenesis and the inflammatory response in macrophages. We show here that Rev-erb-α is highly expressed in oxidative skeletal muscle and plays a role in mitochondrial biogenesis and oxidative function, in gain- and loss-of function studies. Rev-erb-α-deficiency in skeletal muscle leads to reduced mitochondrial content and oxidative function, resulting in compromised exercise capacity. This phenotype was recapitulated in isolated fibers and in muscle cells upon Rev-erbα knock-down, while Rev-erb-α over-expression increased the number of mitochondria with improved respiratory capacity. Rev-erb-α-deficiency resulted in deactivation of the Stk11–Ampk–Sirt1–Ppargc1-α signaling pathway, whereas autophagy was up-regulated, resulting in both impaired mitochondrial biogenesis and increased clearance. Muscle over-expression or pharmacological activation of Rev-erb-α increased respiration and exercise capacity. This study identifies Rev-erb-α as a pharmacological target which improves muscle oxidative function by modulating gene networks controlling mitochondrial number and function.

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          Most cited references 28

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          Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction.

          A new method of total RNA isolation by a single extraction with an acid guanidinium thiocyanate-phenol-chloroform mixture is described. The method provides a pure preparation of undegraded RNA in high yield and can be completed within 4 h. It is particularly useful for processing large numbers of samples and for isolation of RNA from minute quantities of cells or tissue samples.
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            Regulation of Circadian Behavior and Metabolism by Rev-erbα and Rev-erbβ

            The circadian clock acts at the genomic level to coordinate internal behavioral and physiologic rhythms via the CLOCK-BMAL transcriptional heterodimer. Although the nuclear receptors REV-ERBα and β have been proposed to form an accessory feedback loop that contributes to clock function 1,2 , their precise roles and importance remain unresolved. To establish their regulatory potential we generated comparative cistromes of both REV-ERB isoforms, which revealed shared recognition at over 50% of their total sites and extensive overlap with the master circadian regulator BMAL1. While Rev-erbα has been shown to directly regulate Bmal1 expression 1,2 , the cistromic analysis reveals a direct connection between Bmal1 and Rev-erbα and β regulatory circuits than previously suspected. Genes within the intersection of the BMAL1, REV-ERBα and REV-ERBβ cistromes are highly enriched for both clock and metabolic functions. As predicted by the cistromic analysis, dual depletion of Rev-erbα/β function by creating double-knockout mice (DKOs) profoundly disrupted circadian expression of core circadian clock and lipid homeostatic gene networks. As a result, DKOs show strikingly altered circadian wheel-running behavior and deregulated lipid metabolism. These data now ally Rev-erbα/β with Per, Cry and other components of the principal feedback loop that drives circadian expression and suggest a more integral mechanism for the coordination of circadian rhythm and metabolism.
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              Circadian gene expression in individual fibroblasts: cell-autonomous and self-sustained oscillators pass time to daughter cells.

              The mammalian circadian timing system is composed of a central pacemaker in the suprachiasmatic nucleus (SCN) of the brain and subsidiary oscillators in most peripheral cell types. While oscillators in SCN neurons are known to function in a self-sustained fashion, peripheral oscillators have been thought to damp rapidly when disconnected from the control exerted by the SCN. Using two reporter systems, we monitored circadian gene expression in NIH3T3 mouse fibroblasts in real time and in individual cells. In conjunction with mathematical modeling and cell co-culture experiments, these data demonstrated that in vitro cultured fibroblasts harbor self-sustained and cell-autonomous circadian clocks similar to those operative in SCN neurons. Circadian gene expression in fibroblasts continues during cell division, and our experiments unveiled unexpected interactions between the circadian clock and the cell division clock. Specifically, the circadian oscillator gates cytokinesis to defined time windows, and mitosis elicits phase shifts in circadian cycles.
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                Author and article information

                Journal
                9502015
                8791
                Nat Med
                Nat. Med.
                Nature medicine
                1078-8956
                1546-170X
                22 May 2013
                14 July 2013
                August 2013
                01 February 2014
                : 19
                : 8
                : 1039-1046
                Affiliations
                [1 ]Institut Pasteur de Lille, Lille F-59019, France
                [2 ]INSERM UMR 1011 ‘Nuclear Receptors, Cardiovascular Diseases and Diabetes’, Lille F-59019, France
                [3 ]Université Lille Nord de France, Faculté des Sciences Pharmaceutiques et Biologiques et Faculté de Médecine, Lille F-59006, France
                [4 ]UDSL, F-59000, Lille, France
                [5 ]European Genomic Institute for Diabetes (EGID), FR 3508, F-59000 Lille, France
                [6 ]Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, Florida 33458, USA
                [7 ]Département de Physiologie (EA 4484), Faculté de Médecine, Université Lille Nord de France, place de Verdun, Lille cedex 59045, France
                [8 ]School for Nutrition, Toxicology and Metabolism, depts of Human Biology and Human Movement Sciences, Maastricht University Medical Center, NL-6200 MD Maastricht, The Netherlands
                Author notes
                Correspondence to: Hélène Duez or Bart Staels, UR1011 INSERM, Institut Pasteur de Lille, BP 245, 1, rue Calmette, 59019 Lille, France. Bart.Staels@ 123456pasteur-lille.fr ; Helene.Duez@ 123456pasteur-lille.fr
                [*]

                have equally contributed

                Article
                NIHMS472510
                10.1038/nm.3213
                3737409
                23852339

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                Funding
                Funded by: National Institute of Mental Health : NIMH
                Award ID: R01 MH093429 || MH
                Funded by: National Institute of Diabetes and Digestive and Kidney Diseases : NIDDK
                Award ID: R01 DK080201 || DK
                Categories
                Article

                Medicine

                autophagy, mitochondrial biogenesis, oxidative capacity, skeletal muscle, rev-erb-α

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