Genetic analysis of p38 MAP kinases in myogenesis: fundamental role of p38|[alpha]| in abrogating myoblast proliferation

doi:doi:10.1038/sj.emboj.7601587

Article

The EMBO Journal (2007) 26, 1245 - 1256
doi:10.1038/sj.emboj.7601587

Published online: 15 February 2007

Subject Categories:
- Signal Transduction | Differentiation and Death

Genetic analysis of p38 MAP kinases in myogenesis: fundamental role of p38 in abrogating myoblast proliferation

Eusebio Perdiguero^1,^a, Vanessa Ruiz-Bonilla^1,^a, Lionel Gresh^2,^b, Lijian Hui^2,^b, Esteban Ballestar³, Pedro Sousa-Victor¹, Bernat Baeza-Raja¹, Mercè Jardí¹, Anna Bosch-Comas¹, Manel Esteller³, Carme Caelles⁴, Antonio L Serrano¹, Erwin F Wagner² and Pura Muñoz-Cánoves¹

Differentiation and Cancer Program, Center for Genomic Regulation (CRG-PRBB), Barcelona, Spain
Research Institute of Molecular Pathology (IMP), Vienna, Austria
Spanish National Cancer Center (CNIO), Madrid, Spain
Biomedical Research Institute (IRB-PCB), Barcelona, Spain

Correspondence to:

Pura Muñoz-Cánoves, Center for Genomic Regulation (CRG), Program on Differentiation and Cancer, Dr Aiguader, 88, Barcelona 08003, Spain. Tel.: +34 93 3160133; Fax: +34 93 3160099; E-mail: pura.munoz@crg.es

^aThese authors contributed equally to this work

^bThese authors contributed equally to this work

Received 11 August 2006; Accepted 10 January 2007

The p38 mitogen-activated protein kinase (MAPK) pathway plays a critical role in skeletal muscle differentiation. However, the relative contribution of the four p38 MAPKs (p38 alpha , p38 beta , p38 gamma and p38 delta ) to this process is unknown. Here we show that myoblasts lacking p38 alpha , but not those lacking p38 beta or p38 delta , are unable to differentiate and form multinucleated myotubes, whereas p38 gamma -deficient myoblasts exhibit an attenuated fusion capacity. The defective myogenesis in the absence of p38 alpha is caused by delayed cell-cycle exit and continuous proliferation in differentiation-promoting conditions. Indeed, activation of JNK/cJun was enhanced in p38 alpha -deficient myoblasts leading to increased cyclin D1 transcription, whereas inhibition of JNK activity rescued the proliferation phenotype. Thus, p38 alpha controls myogenesis by antagonizing the activation of the JNK proliferation-promoting pathway, before its direct effect on muscle differentiation-specific gene transcription. More importantly, in agreement with the defective myogenesis of cultured p38 alpha ^/ myoblasts, neonatal muscle deficient in p38 alpha shows cellular hyperproliferation and delayed maturation. This study provides novel evidence of a fundamental role of p38 alpha in muscle formation in vitro and in vivo.