MRF4 negatively regulates adult skeletal muscle growth by repressing MEF2 activity

Irene Moretti, Stefano Ciciliot, Kenneth A. Dyar, Reimar Abraham, Marta Murgia, Lisa Agatea, Takayuki Akimoto, Silvio Bicciato, Mattia Forcato, Philippe Pierre, N. Henriette Uhlenhaut, Peter W. J. Rigby, Jaime J. Carvajal, Bert Blaauw, Elisa Calabria () and Stefano Schiaffino ()
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Irene Moretti: Venetian Institute of Molecular Medicine (VIMM)
Stefano Ciciliot: Venetian Institute of Molecular Medicine (VIMM)
Kenneth A. Dyar: Molecular Endocrinology, Institute for Diabetes and Obesity, Helmholtz Zentrum München, Business Campus Garching
Reimar Abraham: Venetian Institute of Molecular Medicine (VIMM)
Marta Murgia: University of Padova
Lisa Agatea: Venetian Institute of Molecular Medicine (VIMM)
Takayuki Akimoto: Venetian Institute of Molecular Medicine (VIMM)
Silvio Bicciato: Center for Genome Research, University of Modena and Reggio Emilia
Mattia Forcato: Center for Genome Research, University of Modena and Reggio Emilia
Philippe Pierre: Centre d’Immunologie de Marseille-Luminy, Aix-Marseille Université, INSERM, CNRS
N. Henriette Uhlenhaut: Molecular Endocrinology, Institute for Diabetes and Obesity, Helmholtz Zentrum München, Business Campus Garching
Peter W. J. Rigby: The Institute of Cancer Research
Jaime J. Carvajal: Molecular Embryology Team, Centro Andaluz de Biología del Desarrollo
Bert Blaauw: Venetian Institute of Molecular Medicine (VIMM)
Elisa Calabria: Venetian Institute of Molecular Medicine (VIMM)
Stefano Schiaffino: Venetian Institute of Molecular Medicine (VIMM)

Nature Communications, 2016, vol. 7, issue 1, 1-12

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms12397

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