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Genetic analysis of p38 MAP kinases in myogenesis: fundamental role of p38alpha in abrogating myoblast proliferation.

ABSTRACT: 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 (p38alpha, p38beta, p38gamma and p38delta) to this process is unknown. Here we show that myoblasts lacking p38alpha, but not those lacking p38beta or p38delta, are unable to differentiate and form multinucleated myotubes, whereas p38gamma-deficient myoblasts exhibit an attenuated fusion capacity. The defective myogenesis in the absence of p38alpha is caused by delayed cell-cycle exit and continuous proliferation in differentiation-promoting conditions. Indeed, activation of JNK/cJun was enhanced in p38alpha-deficient myoblasts leading to increased cyclin D1 transcription, whereas inhibition of JNK activity rescued the proliferation phenotype. Thus, p38alpha 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 p38alpha(Delta/Delta) myoblasts, neonatal muscle deficient in p38alpha shows cellular hyperproliferation and delayed maturation. This study provides novel evidence of a fundamental role of p38alpha in muscle formation in vitro and in vivo.

SUBMITTER: Perdiguero E

PROVIDER: S-EPMC1817635 | biostudies-literature | 2007 Mar

REPOSITORIES: biostudies-literature

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Genetic analysis of p38 MAP kinases in myogenesis: fundamental role of p38alpha in abrogating myoblast proliferation.

Perdiguero Eusebio E Ruiz-Bonilla Vanessa V Gresh Lionel L Hui Lijian L Ballestar Esteban E Sousa-Victor Pedro P Baeza-Raja Bernat B Jardí Mercè M Bosch-Comas Anna A Esteller Manel M Caelles Carme C Serrano Antonio L AL Wagner Erwin F EF Muñoz-Cánoves Pura P

The EMBO journal 20070215 5

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 (p38alpha, p38beta, p38gamma and p38delta) to this process is unknown. Here we show that myoblasts lacking p38alpha, but not those lacking p38beta or p38delta, are unable to differentiate and form multinucleated myotubes, whereas p38gamma-deficient myoblasts exhibit an attenuated fusion capacity. The defective myogenesis in the ...[more]

PMID: 17304211

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Project description:BackgroundTyrosine kinase inhibitors (TKIs) are effective therapies with demonstrated antineoplastic activity. Nilotinib is a second-generation FDA-approved TKI designed to overcome Imatinib resistance and intolerance in patients with chronic myelogenous leukemia (CML). Interestingly, TKIs have also been shown to be an efficient treatment for several non-malignant disorders such fibrotic diseases, including those affecting skeletal muscles.MethodsWe investigated the role of Nilotinib on skeletal myogenesis using the well-established C2C12 myoblast cell line. We evaluated the impact of Nilotinib during the time course of skeletal myogenesis. We compared the effect of Nilotinib with the well-known p38 MAPK inhibitor SB203580. MEK1/2 UO126 and PI3K/AKT LY294002 inhibitors were used to identify the signaling pathways involved in Nilotinib-related effects on myoblast. Adult primary myoblasts were also used to corroborate the inhibition of myoblasts fusion and myotube-nuclei positioning by Nilotinib.ResultsWe found that Nilotinib inhibited myogenic differentiation, reducing the number of myogenin-positive myoblasts and decreasing myogenin and MyoD expression. Furthermore, Nilotinib-mediated anti-myogenic effects impair myotube formation, myosin heavy chain expression, and compromise myotube-nuclei positioning. In addition, we found that p38 MAPK is a new off-target protein of Nilotinib, which causes inhibition of p38 phosphorylation in a similar manner as the well-characterized p38 inhibitor SB203580. Nilotinib induces the activation of ERK1/2 and AKT on myoblasts but not in myotubes. We also found that Nilotinib stimulates myoblast proliferation, a process dependent on ERK1/2 and AKT activation.ConclusionsOur findings suggest that Nilotinib may have important negative effects on muscle homeostasis, inhibiting myogenic differentiation but stimulating myoblasts proliferation. Additionally, we found that Nilotinib stimulates the activation of ERK1/2 and AKT. On the other hand, we suggest that p38 MAPK is a new off-target of Nilotinib. Thus, there is a necessity for future studies to investigate the long-term effects of TKIs on skeletal muscle homeostasis, along with potential detrimental effects in cell differentiation and proliferation in patients receiving TKI therapies.

Dataset Information

Genetic analysis of p38 MAP kinases in myogenesis: fundamental role of p38alpha in abrogating myoblast proliferation.

Publications

Genetic analysis of p38 MAP kinases in myogenesis: fundamental role of p38alpha in abrogating myoblast proliferation.

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