title: Histone deacetylase 6 is a FoxO transcription factor-dependent effector in skeletal muscle atrophy.
abstract: Skeletal muscle atrophy is a severe condition of muscle mass loss. Muscle atrophy is caused by a down-regulation of protein synthesis and by an increase of protein breakdown due to the ubiquitin-proteasome system and autophagy activation. Up-regulation of specific genes, such as the muscle-specific E3 ubiquitin ligase MAFbx, by FoxO transcription factors is essential to initiate muscle protein ubiquitination and degradation during atrophy. HDAC6 is a particular HDAC, which is functionally related to the ubiquitin proteasome system via its ubiquitin binding domain. We show that HDAC6 is up-regulated during muscle atrophy. HDAC6 activation is dependent on the transcription factor FoxO3a, and the inactivation of HDAC6 in mice protects against muscle wasting. HDAC6 is able to interact with MAFbx, a key ubiquitin ligase involved in muscle atrophy. Our findings demonstrate the implication of HDAC6 in skeletal muscle wasting and identify HDAC6 as a new downstream target of FoxO3a in stress response. This work provides new insights in skeletal muscle atrophy development and opens interesting perspectives on HDAC6 as a valuable marker of muscle atrophy and a potential target for pharmacological treatments.
authors.affiliation: From the Ecole Normale Supérieure de Lyon; CNRS UMR 5239; Equipe Différenciation Neuromusculaire, Université de Lyon, 46 allée d'Italie 69364 Lyon cedex 07, France, Université Lyon 1; Hospices civils de Lyon.
authors.forename: Francesca
authors.initials: F
authors.lastname: Ratti
authors.affiliation: From the Ecole Normale Supérieure de Lyon; CNRS UMR 5239; Equipe Différenciation Neuromusculaire, Université de Lyon, 46 allée d'Italie 69364 Lyon cedex 07, France, Université Lyon 1; Hospices civils de Lyon.
authors.forename: Francis
authors.initials: F
authors.lastname: Ramond
authors.affiliation: From the Ecole Normale Supérieure de Lyon; CNRS UMR 5239; Equipe Différenciation Neuromusculaire, Université de Lyon, 46 allée d'Italie 69364 Lyon cedex 07, France, Université Lyon 1; Hospices civils de Lyon.
authors.forename: Vincent
authors.initials: V
authors.lastname: Moncollin
authors.affiliation: From the Ecole Normale Supérieure de Lyon; CNRS UMR 5239; Equipe Différenciation Neuromusculaire, Université de Lyon, 46 allée d'Italie 69364 Lyon cedex 07, France, Université Lyon 1; Hospices civils de Lyon.
authors.forename: Thomas
authors.initials: T
authors.lastname: Simonet
authors.affiliation: Department of Biomedical Sciences, University of Padova, 35131 Padova, Italy, and Dulbecco Telethon Institute, Venetian Institute of Molecular Medicine, 35129 Padova, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Milan
authors.affiliation: From the Ecole Normale Supérieure de Lyon; CNRS UMR 5239; Equipe Différenciation Neuromusculaire, Université de Lyon, 46 allée d'Italie 69364 Lyon cedex 07, France, Université Lyon 1; Hospices civils de Lyon.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Méjat
authors.affiliation: From the Ecole Normale Supérieure de Lyon; CNRS UMR 5239; Equipe Différenciation Neuromusculaire, Université de Lyon, 46 allée d'Italie 69364 Lyon cedex 07, France, Université Lyon 1; Hospices civils de Lyon.
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Thomas
authors.affiliation: Université Lyon 1; Hospices civils de Lyon.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Streichenberger
authors.affiliation: INSERM U309, Institut Albert Bonniot, 38706 La Tronche Cedex, France.
authors.forename: Benoit
authors.initials: B
authors.lastname: Gilquin
authors.affiliation: Friedrich Miescher Institute, Maulbeerstrasse 66, 4058 Basel, Switzerland.
authors.forename: Patrick
authors.initials: P
authors.lastname: Matthias
authors.affiliation: INSERM U309, Institut Albert Bonniot, 38706 La Tronche Cedex, France.
authors.forename: Saadi
authors.initials: S
authors.lastname: Khochbin
authors.affiliation: Department of Biomedical Sciences, University of Padova, 35131 Padova, Italy, and Dulbecco Telethon Institute, Venetian Institute of Molecular Medicine, 35129 Padova, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Sandri
authors.affiliation: From the Ecole Normale Supérieure de Lyon; CNRS UMR 5239; Equipe Différenciation Neuromusculaire, Université de Lyon, 46 allée d'Italie 69364 Lyon cedex 07, France, Université Lyon 1; Hospices civils de Lyon, Laurent.Schaeffer@ens-lyon.fr.
authors.forename: Laurent
authors.initials: L
authors.lastname: Schaeffer
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D024202:Electrophoretic Mobility Shift Assay; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D047468:Immunoprecipitation; D019426:Integrases / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009121:Muscle Denervation; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology*; D009133:Muscular Atrophy / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C045073:Cre recombinase; D019426:Integrases; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases
keywords: FOXO; Histone Deacetylase 6 (HDAC6); MAFbx; Muscle Atrophy; Proteasome; Skeletal Muscle; Ubiquitin