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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 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-α deficiency resulted in deactivation of the Lkb1-Ampk-Sirt1–Ppargc-1α signaling pathway. These effects were recapitulated in isolated fibers and in muscle cells after knockdown of the gene encoding Rev-erb-α, Nr1d1. In complementary experiments, Rev-erb-α overexpression in vitro increased the number of mitochondria and improved respiratory capacity, whereas muscle overexpression or pharmacological activation of Rev-erb-α in vivo increased exercise capacity. This study identifies Rev-erb-α as a pharmacological target that improves muscle oxidative function by modulating gene networks controlling mitochondrial number and function.

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Figure 1: Nr1d1−/− mice have reduced voluntary activity and exercise performance.
Figure 2: Rev-erb-α modulates mitochondrial content and function.
Figure 3: Rev-erb-α modulates mitochondrial respiration.
Figure 4: Rev-erb-α modulates mitochondrial biogenesis by interfering with Ampk–Sirt1–Ppargc-1α signaling.
Figure 5: Rev-erb-α modulates skeletal muscle autophagy.
Figure 6: Rev-erb-α overexpression or pharmacological activity improves mitochondrial function and exercise capacity.

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Acknowledgements

This research was supported by a Marie Curie International Reintegration Grant (FP7) (to H.D.), the European Commission (FP7) consortium Eurhythdia (to B.S.), Région Nord Pas-de-Calais/Fonds Européen de Développement Régional (to B.S.), a Contrat de Projet Etat-Région 'starting grant' (to H.D.), the European Genomic Institute for Diabetes (EGID, ANR-10-LABX-46) (to B.S.), an unrestricted Instituts Thématiques Multi-Organismes/Astra Zeneca grant (to B.S.), a joint Société Francophone du Diabète/Merck Sharp & Dohme research fellowship (to H.D.), a research grant from the European Foundation for the Study of Diabetes/Lilly (to H.D.), US National Institutes of Health grants (MH093429 and DK080201) (to T.P.B.), a National Research Service Award (DK088499) (to L.A.S.) and a VICI research grant for innovative research from the Netherlands Organization for Scientific Research (918.96.618) (to P.S.). B.S. receives support from the Institut Universitaire de France.

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E.W., Y. Sebti, B.S. and H.D. were responsible for the study design, data analysis and interpretation and wrote the manuscript. E.W., Y. Sebti, L.A.S., C.D., S.L., C.P., S.D., G.S. and R.N. performed the experiments and data analysis. J.E., P.L., M.K.C.H., P.S. and T.P.B. were involved in data analysis. Y. Shin and T.M.K. were involved in Rev-erb-α ligand chemistry.

Corresponding authors

Correspondence to Bart Staels or Hélène Duez.

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The authors declare no competing financial interests.

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Woldt, E., Sebti, Y., Solt, L. et al. Rev-erb-α modulates skeletal muscle oxidative capacity by regulating mitochondrial biogenesis and autophagy. Nat Med 19, 1039–1046 (2013). https://doi.org/10.1038/nm.3213

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