title: REDD1 deletion prevents dexamethasone-induced skeletal muscle atrophy.
abstract: REDD1 (regulated in development and DNA damage response 1) has been proposed to inhibit the mechanistic target of rapamycin complex 1 (mTORC1) during in vitro hypoxia. REDD1 expression is low under basal conditions but is highly increased in response to several catabolic stresses, like hypoxia and glucocorticoids. However, REDD1 function seems to be tissue and stress dependent, and its role in skeletal muscle in vivo has been poorly characterized. Here, we investigated the effect of REDD1 deletion on skeletal muscle mass, protein synthesis, proteolysis, and mTORC1 signaling pathway under basal conditions and after glucocorticoid administration. Whereas skeletal muscle mass and typology were unchanged between wild-type (WT) and REDD1-null mice, oral gavage with dexamethasone (DEX) for 7 days reduced tibialis anterior and gastrocnemius muscle weights as well as tibialis anterior fiber size only in WT. Similarly, REDD1 deletion prevented the inhibition of protein synthesis and mTORC1 activity (assessed by S6, 4E-BP1, and ULK1 phosphorylation) observed in gastrocnemius muscle of WT mice following single DEX administration for 5 h. However, our results suggest that REDD1-mediated inhibition of mTORC1 in skeletal muscle is not related to the modulation of the binding between TSC2 and 14-3-3. In contrast, our data highlight a new mechanism involved in mTORC1 inhibition linking REDD1, Akt, and PRAS40. Altogether, these results demonstrated in vivo that REDD1 is required for glucocorticoid-induced inhibition of protein synthesis via mTORC1 downregulation. Inhibition of REDD1 may thus be a strategy to limit muscle loss in glucocorticoid-mediated atrophy.
authors.affiliation: Institut National de la Recherche Agronomique, UMR 866 Dynamique Musculaire et Métabolisme, F-34000 Montpellier, France; Université Montpellier 1, F-34000 Montpellier, France; Université Montpellier 2, F-34000 Montpellier, France;
authors.forename: Florian A
authors.initials: FA
authors.lastname: Britto
authors.affiliation: Institut National de la Recherche Agronomique, UMR 866 Dynamique Musculaire et Métabolisme, F-34000 Montpellier, France; Université Montpellier 1, F-34000 Montpellier, France; Université Montpellier 2, F-34000 Montpellier, France;
authors.forename: Gwenaelle
authors.initials: G
authors.lastname: Begue
authors.affiliation: Institut National de la Recherche Agronomique, UMR 866 Dynamique Musculaire et Métabolisme, F-34000 Montpellier, France; Université Montpellier 1, F-34000 Montpellier, France; Université Montpellier 2, F-34000 Montpellier, France;
authors.forename: Bernadette
authors.initials: B
authors.lastname: Rossano
authors.affiliation: Institut National de la Recherche Agronomique, UMR 866 Dynamique Musculaire et Métabolisme, F-34000 Montpellier, France; Université Montpellier 1, F-34000 Montpellier, France; Université Montpellier 2, F-34000 Montpellier, France;
authors.forename: Aurélie
authors.initials: A
authors.lastname: Docquier
authors.affiliation: Institut National de la Recherche Agronomique, UMR 866 Dynamique Musculaire et Métabolisme, F-34000 Montpellier, France; Université Montpellier 1, F-34000 Montpellier, France; Université Montpellier 2, F-34000 Montpellier, France;
authors.forename: Barbara
authors.initials: B
authors.lastname: Vernus
authors.affiliation: Institut National de la Sante et de la Recherche Medicale (INSERM) U 583, Institut de Neuroscience de Montpellier, France;
authors.forename: Chamroeun
authors.initials: C
authors.lastname: Sar
authors.affiliation: Institut de Myologie, INSERM, U974, Centre National de la Recherche Scientifique UMR 7215, Université Pierre et Marie Curie, Paris, France; and Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Ferry
authors.affiliation: Institut National de la Recherche Agronomique, UMR 866 Dynamique Musculaire et Métabolisme, F-34000 Montpellier, France; Université Montpellier 1, F-34000 Montpellier, France; Université Montpellier 2, F-34000 Montpellier, France;
authors.forename: Anne
authors.initials: A
authors.lastname: Bonnieu
authors.affiliation: Institut National de la Recherche Agronomique, UMR 866 Dynamique Musculaire et Métabolisme, F-34000 Montpellier, France; Université Montpellier 1, F-34000 Montpellier, France; Université Montpellier 2, F-34000 Montpellier, France;
authors.forename: Vincent
authors.initials: V
authors.lastname: Ollendorff
authors.affiliation: Institut National de la Recherche Agronomique, UMR 866 Dynamique Musculaire et Métabolisme, F-34000 Montpellier, France; Université Montpellier 1, F-34000 Montpellier, France; Université Montpellier 2, F-34000 Montpellier, France; favier@supagro.inra.fr.
authors.forename: François B
authors.initials: FB
authors.lastname: Favier
mesh_terms: D000818:Animals; D003345:Corticosterone / Q000378:metabolism; D003907:Dexamethasone; D005243:Feces / Q000737:chemistry; D005260:Female; D051379:Mice; D009119:Muscle Contraction / Q000502:physiology; D018482:Muscle, Skeletal / Q000473:pathology; D009133:Muscular Atrophy / Q000139:chemically induced* / Q000235:genetics* / Q000473:pathology; D059748:Proteolysis; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics* / Q000502:physiology*
chemical_list: C469992:Ddit4 protein, mouse; D012333:RNA, Messenger; D014157:Transcription Factors; D003907:Dexamethasone; D003345:Corticosterone
keywords: autophagy; glucocorticoids; mechanistic target of rapamycin; proline-rich Akt substrate of 40 kDa; protein synthesis; regulated in development and DNA damage response 1