MRF4 negatively regulates adult skeletal muscle growth by repressing MEF2 activity

Irene Moretti (1) , Stefano Ciciliot (1) , Kenneth A. Dyar (2) , Reimar Abraham (1) , Marta Murgia (3) , Lisa Agatea (1) , Takayuki Akimoto (1) , Silvio Bicciato (4) , Mattia Forcato (4) , Philippe Pierre (5) , N. Henriette Uhlenhaut (2) , Peter W. J. Rigby (6) , Jaime J. Carvajal (7) , Bert Blaauw (1) , Elisa Calabria (1) , Stefano Schiaffino (1)

1 VIMM - Venetian Institute Molecular Medicine
2 Helmholtz Zentrum München = German Research Center for Environmental Health
3 Unipd - Università degli Studi di Padova = University of Padua
4 University - Hospital of Modena and Reggio Emilia [Modena, Italy]
5 CIML - Centre d'Immunologie de Marseille - Luminy
6 Chester Beatty Laboratories
7 Centro Andaluz de Biologia del Desarrollo

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.

Mots clés: Cell growth; Skeletal muscle

Domaines: Immunologie

Irene Moretti, Stefano Ciciliot, Kenneth A. Dyar, Reimar Abraham, Marta Murgia, et al.. MRF4 negatively regulates adult skeletal muscle growth by repressing MEF2 activity. Nature Communications, 2016, 7, ⟨10.1038/ncomms12397⟩. ⟨hal-01438131⟩