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MRF4 negatively regulates adult skeletal muscle growth by repressing MEF2 activity

Author

Listed:
  • 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
    Present address: Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Am Klopferspitz 18, 82152 Martinsried, Germany)

  • Lisa Agatea

    (Venetian Institute of Molecular Medicine (VIMM))

  • Takayuki Akimoto

    (Venetian Institute of Molecular Medicine (VIMM)
    Present address: Faculty of Sport Sciences, Waseda University, Mikajima 2-579-15, Tokorozawa, Saitama 359-1192, Japan)

  • 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
    Institute for Research in Biomedicine (iBiMED), and Aveiro Health Sciences Program, University of Aveiro)

  • 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)
    University of Padova)

  • Elisa Calabria

    (Venetian Institute of Molecular Medicine (VIMM)
    Present address: Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Piazzale L.A. Scuro 10, 37134 Verona, Italy)

  • Stefano Schiaffino

    (Venetian Institute of Molecular Medicine (VIMM))

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.

Suggested Citation

  • Irene Moretti & Stefano Ciciliot & Kenneth A. Dyar & Reimar Abraham & Marta Murgia & Lisa Agatea & Takayuki Akimoto & Silvio Bicciato & Mattia Forcato & Philippe Pierre & N. Henriette Uhlenhaut & Pete, 2016. "MRF4 negatively regulates adult skeletal muscle growth by repressing MEF2 activity," Nature Communications, Nature, vol. 7(1), pages 1-12, November.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms12397
    DOI: 10.1038/ncomms12397
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