MRF4 negatively regulates adult skeletal muscle growth by repressing MEF2 activity

被引：88

作者：

Moretti, Irene ^{[1
]}

Ciciliot, Stefano ^{[1
]}

Dyar, Kenneth A. ^{[2
]}

Abraham, Reimar ^{[1
]}

Murgia, Marta ^{[3
,10
]}

Agatea, Lisa ^{[1
]}

Akimoto, Takayuki ^{[1
,11
]}

Bicciato, Silvio ^{[4
]}

Forcato, Mattia ^{[4
]}

Pierre, Philippe ^{[5
,6
,7
]}

Uhlenhaut, N. Henriette ^{[2
]}

Rigby, Peter W. J. ^{[8
]}

Carvajal, Jaime J. ^{[9
]}

Blaauw, Bert ^{[1
,3
]}

Calabria, Elisa ^{[1
,12
]}

Schiaffino, Stefano ^{[1
]}

机构：

[1] VIMM, Via Orus 2, I-35129 Padua, Italy

[2] Helmholtz Zentrum Munchen, Inst Diabet & Obes, Mol Endocrinol, Business Campus Garching,Pk Ring 13, D-85748 Garching, Germany

[3] Univ Padua, Dept Biomed Sci, Via Ugo Bassi 58-B, I-35131 Padua, Italy

[4] Univ Modena & Reggio Emilia, Dept Life Sci, Ctr Genome Res, Via Campi 287, I-41125 Modena, Italy

[5] Aix Marseille Univ, INSERM, CNRS, Ctr Immunol Marseille Luminy, F-13288 Marseille, France

[6] Univ Aveiro, Inst Res Biomed iBiMED, P-3810193 Aveiro, Portugal

[7] Univ Aveiro, Aveiro Hlth Sci Program, P-3810193 Aveiro, Portugal

[8] Chester Beatty Labs, Inst Canc Res, Div Canc Biol, 237,Fulham Rd, London SW3 61B, England

[9] CSIC UPO JA, Ctr Andaluz Biol Desarrollo, Mol Embryol Team, Carretera Utrera Km1, Seville 41013, Spain

[10] Max Planck Inst Biochem, Dept Prote & Signal Transduct, Klopferspitz 18, D-82152 Martinsried, Germany

[11] Waseda Univ, Fac Sport Sci, Mikajima 2-579-15, Tokorozawa, Saitama 3591192, Japan

[12] Univ Verona, Dept Neurosci Biomed & Movement Sci, Piazzale LA Scuro 10, I-37134 Verona, Italy

来源：

NATURE COMMUNICATIONS | 2016年 / 7卷

关键词：

MYOSIN HEAVY-CHAIN; TRANSCRIPTION FACTORS; GENE-EXPRESSION; HEART-FAILURE; MYOGENIN; ACTIVATION; HDAC4; DIFFERENTIATION; REGENERATION; DYSFUNCTION;

D O I：

10.1038/ncomms12397

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：12

共 52 条

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