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, Stefano Schiaffino

Research output: Contribution to journalArticle

26 Citations (Scopus)

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.

Original languageEnglish
Article number12397
JournalNature Communications
Volume7
DOIs
Publication statusPublished - 2016 Aug 3

Fingerprint

skeletal muscle
RNA Interference
muscles
genes
Muscle
Skeletal Muscle
Muscles
Hypertrophy
Genes
Myogenic Regulatory Factors
Growth
MEF2 Transcription Factors
Sarcopenia
atrophy
protein synthesis
Co-Repressor Proteins
Cachexia
ranking
Denervation
Atrophy

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Moretti, I., Ciciliot, S., Dyar, K. A., Abraham, R., Murgia, M., Agatea, L., ... Schiaffino, S. (2016). MRF4 negatively regulates adult skeletal muscle growth by repressing MEF2 activity. Nature Communications, 7, [12397]. https://doi.org/10.1038/ncomms12397

MRF4 negatively regulates adult skeletal muscle growth by repressing MEF2 activity. / Moretti, Irene; Ciciliot, Stefano; Dyar, Kenneth A.; Abraham, Reimar; Murgia, Marta; Agatea, Lisa; Akimoto, Takayuki; Bicciato, Silvio; Forcato, Mattia; Pierre, Philippe; Uhlenhaut, N. Henriette; Rigby, Peter W J; Carvajal, Jaime J.; Blaauw, Bert; Calabria, Elisa; Schiaffino, Stefano.

In: Nature Communications, Vol. 7, 12397, 03.08.2016.

Research output: Contribution to journalArticle

Moretti, I, Ciciliot, S, Dyar, KA, Abraham, R, Murgia, M, Agatea, L, Akimoto, T, Bicciato, S, Forcato, M, Pierre, P, Uhlenhaut, NH, Rigby, PWJ, Carvajal, JJ, Blaauw, B, Calabria, E & Schiaffino, S 2016, 'MRF4 negatively regulates adult skeletal muscle growth by repressing MEF2 activity', Nature Communications, vol. 7, 12397. https://doi.org/10.1038/ncomms12397
Moretti I, Ciciliot S, Dyar KA, Abraham R, Murgia M, Agatea L et al. MRF4 negatively regulates adult skeletal muscle growth by repressing MEF2 activity. Nature Communications. 2016 Aug 3;7. 12397. https://doi.org/10.1038/ncomms12397
Moretti, Irene ; Ciciliot, Stefano ; Dyar, Kenneth A. ; Abraham, Reimar ; Murgia, Marta ; Agatea, Lisa ; Akimoto, Takayuki ; Bicciato, Silvio ; Forcato, Mattia ; Pierre, Philippe ; Uhlenhaut, N. Henriette ; Rigby, Peter W J ; Carvajal, Jaime J. ; Blaauw, Bert ; Calabria, Elisa ; Schiaffino, Stefano. / MRF4 negatively regulates adult skeletal muscle growth by repressing MEF2 activity. In: Nature Communications. 2016 ; Vol. 7.
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