title: MRF4 negatively regulates adult skeletal muscle growth by repressing MEF2 activity.
abstract: The myogenic regulatory factor MRF4 is highly expressed in adult skeletal muscle but its function is unknown. Here we show that Mrf4 knockdown in adult muscle induces hypertrophy and prevents denervation-induced atrophy. This effect is accompanied by increased protein synthesis and widespread activation of muscle-specific genes, many of which are targets of MEF2 transcription factors. MEF2-dependent genes represent the top-ranking gene set enriched after Mrf4 RNAi and a MEF2 reporter is inhibited by co-transfected MRF4 and activated by Mrf4 RNAi. The Mrf4 RNAi-dependent increase in fibre size is prevented by dominant negative MEF2, while constitutively active MEF2 is able to induce myofibre hypertrophy. The nuclear localization of the MEF2 corepressor HDAC4 is impaired by Mrf4 knockdown, suggesting that MRF4 acts by stabilizing a repressor complex that controls MEF2 activity. These findings open new perspectives in the search for therapeutic targets to prevent muscle wasting, in particular sarcopenia and cachexia.
authors.affiliation: Venetian Institute of Molecular Medicine (VIMM), via Orus 2, 35129 Padova, Italy.
authors.forename: Irene
authors.initials: I
authors.lastname: Moretti
authors.affiliation: Venetian Institute of Molecular Medicine (VIMM), via Orus 2, 35129 Padova, Italy.
authors.forename: Stefano
authors.identifier: 0000-0002-5833-6581
authors.initials: S
authors.lastname: Ciciliot
authors.affiliation: Molecular Endocrinology, Institute for Diabetes and Obesity, Helmholtz Zentrum München, Business Campus Garching, Parkring 13, D-85748 Garching, Germany.
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Dyar
authors.affiliation: Venetian Institute of Molecular Medicine (VIMM), via Orus 2, 35129 Padova, Italy.
authors.forename: Reimar
authors.initials: R
authors.lastname: Abraham
authors.affiliation: Department of Biomedical Sciences, University of Padova, via Ugo Bassi 58/B, 35131 Padova, Italy.
authors.forename: Marta
authors.initials: M
authors.lastname: Murgia
authors.affiliation: Venetian Institute of Molecular Medicine (VIMM), via Orus 2, 35129 Padova, Italy.
authors.forename: Lisa
authors.initials: L
authors.lastname: Agatea
authors.affiliation: Venetian Institute of Molecular Medicine (VIMM), via Orus 2, 35129 Padova, Italy.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Akimoto
authors.affiliation: Center for Genome Research, Department of Life Sciences, University of Modena and Reggio Emilia, Via Campi 287, 41125 Modena, Italy.
authors.forename: Silvio
authors.identifier: 0000-0002-1944-7078
authors.initials: S
authors.lastname: Bicciato
authors.affiliation: Center for Genome Research, Department of Life Sciences, University of Modena and Reggio Emilia, Via Campi 287, 41125 Modena, Italy.
authors.forename: Mattia
authors.identifier: 0000-0002-7383-6576
authors.initials: M
authors.lastname: Forcato
authors.affiliation: Centre d'Immunologie de Marseille-Luminy, Aix-Marseille Université, INSERM, CNRS, 13288, Marseille, France.|Institute for Research in Biomedicine (iBiMED), and Aveiro Health Sciences Program, University of Aveiro, 3810-193 Aveiro, Portugal.
authors.forename: Philippe
authors.initials: P
authors.lastname: Pierre
authors.affiliation: Molecular Endocrinology, Institute for Diabetes and Obesity, Helmholtz Zentrum München, Business Campus Garching, Parkring 13, D-85748 Garching, Germany.
authors.forename: N Henriette
authors.initials: NH
authors.lastname: Uhlenhaut
authors.affiliation: Division of Cancer Biology, The Institute of Cancer Research, Chester Beatty Laboratories, 237, Fulham Road, London SW3 61B, UK.
authors.forename: Peter W J
authors.initials: PW
authors.lastname: Rigby
authors.affiliation: Molecular Embryology Team, Centro Andaluz de Biología del Desarrollo, CSIC-UPO-JA, Carretera de Utrera Km1, 41013 Seville, Spain.
authors.forename: Jaime J
authors.initials: JJ
authors.lastname: Carvajal
authors.affiliation: Venetian Institute of Molecular Medicine (VIMM), via Orus 2, 35129 Padova, Italy.|Department of Biomedical Sciences, University of Padova, via Ugo Bassi 58/B, 35131 Padova, Italy.
authors.forename: Bert
authors.initials: B
authors.lastname: Blaauw
authors.affiliation: Venetian Institute of Molecular Medicine (VIMM), via Orus 2, 35129 Padova, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Calabria
authors.affiliation: Venetian Institute of Molecular Medicine (VIMM), via Orus 2, 35129 Padova, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Schiaffino
mesh_terms: D021581:Active Transport, Cell Nucleus; D000375:Aging / Q000378:metabolism*; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D020869:Gene Expression Profiling; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D006984:Hypertrophy; D064326:MEF2 Transcription Factors / Q000378:metabolism*; D008297:Male; D018485:Muscle Fibers, Skeletal / Q000378:metabolism / Q000473:pathology; D018482:Muscle, Skeletal / Q000254:growth & development* / Q000378:metabolism* / Q000473:pathology; D018006:Myogenic Regulatory Factors / Q000378:metabolism*; D009928:Organ Specificity / Q000235:genetics; D011485:Protein Binding; D014176:Protein Biosynthesis; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D017208:Rats, Wistar; D012097:Repressor Proteins / Q000378:metabolism; D014158:Transcription, Genetic; D015854:Up-Regulation / Q000235:genetics
chemical_list: D064326:MEF2 Transcription Factors; D018006:Myogenic Regulatory Factors; D034741:RNA, Small Interfering; D012097:Repressor Proteins; C063403:myogenic factor 6; C400300:HDAC4 protein, human; D006655:Histone Deacetylases