Trends in Cell Biology
Volume 16, Issue 1, January 2006, Pages 36-44
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Regulation of skeletal muscle gene expression by p38 MAP kinases

https://doi.org/10.1016/j.tcb.2005.11.002Get rights and content

The formation of skeletal muscle is a multistep process orchestrated by the basic helix–loop–helix myogenic regulatory factors (MRFs). A wide array of proteins can interact with the MRFs, resulting in either induction or repression of their myogenic potential and subsequent MRF-mediated muscle-specific transcription. Findings published over the past few years have unambiguously established a key role for the p38 MAP kinase pathway in the control of muscle gene expression at different stages of the myogenic process. Here, we discuss the mechanisms by which p38 MAP kinase controls skeletal muscle differentiation by regulating the sequential activation of MRFs and their transcriptional coactivators, including chromatin remodeling enzymes.

Introduction

The regulation of skeletal muscle formation (myogenesis) is essential for normal development as well as in pathological conditions such as muscular dystrophies and inflammatory myopathies. Myogenesis is a dynamic process in which mononucleated undifferentiated myoblasts first proliferate, then withdraw from the cell cycle and finally differentiate and fuse to form the multinucleated mature muscle fiber. This process is controlled by members of a family of muscle-specific basic helix–loop–helix (bHLH) proteins that, in concert with members of the ubiquitous E2A and myocyte enhancer factor-2 (MEF2) families, activate the differentiation program by inducing transcription of regulatory and structural muscle-specific genes [1] (Figure 1). Additional levels of regulation impinge on this basic transcriptional model to provide further versatility to muscle gene expression. The question of how these signals are deciphered by the myogenic effectors has been the center of intensive investigation. A signaling pathway that plays a fundamental role in the transition of myoblasts to differentiated myocytes involves p38 mitogen-activated protein kinase (MAPK). Recent studies have demonstrated that p38 MAPK provides a link between the myogenic transcription factors that activate muscle genes directly and the chromatin remodeling activities associated with the muscle differentiation program. Here, we discuss how p38 MAPK controls the transcriptional circuitry that underlies tissue-specific gene expression, with particular emphasis on skeletal muscle.

Section snippets

Regulation of skeletal muscle gene expression by myogenic regulatory factors

Activation of muscle differentiation-specific genes is controlled by the myogenic regulatory factors (MRFs), which belong to the bHLH family of transcription factors (Figure 2). The MRF family consists of four members: Myf5, MyoD, myogenin and MRF4, all of which bind to sequence-specific DNA elements (E box: …CANNTG…) present in the promoters of muscle genes. Selective and productive recognition of E boxes on muscle promoters requires heterodimerization of MyoD with ubiquitously expressed bHLH

Interaction of MRFs with transcriptional cofactors

The MRFs have the unique property of converting non-muscle cells to the muscle lineage, strongly suggesting that they can, directly or indirectly, induce relaxation of the otherwise-repressed chromatin on their target genes. The potential of MyoD to stimulate muscle-specific gene transcription derives both from its intrinsic ability to reorganize chromatin through a region rich in histidine and cysteine residues (H/C domain), which lies N-terminal to the basic region, and a potential

Requirement for p38 MAPK activity in skeletal muscle differentiation

Independent studies have unambiguously demonstrated that the p38 MAPK signaling pathway (Box 2) is a crucial regulator of skeletal muscle differentiation. Treatment with the p38α and p38β inhibitor SB203580 prevented the fusion of myoblasts into myotubes, as well as the induction of muscle-specific genes 21, 22, 23, 24. Importantly, a recent report has shown the requirement for p38α/p38β in the activation of the quiescent satellite cell (the muscle stem cell), although the mechanism underlying

p38 MAPK-regulated mechanisms controlling muscle-specific gene transcription

While p38 MAPK plays an essential role in myoblast differentiation, the underlying molecular mechanisms of muscle-specific transcriptional control by p38 MAPKs remain largely unknown.

Concluding remarks

The formation of skeletal muscle is a well-orchestrated multistep process controlled by the MRF family of transcription factors. Several cofactors enhance or repress the myogenic potential of the MRFs, either directly or indirectly, thus influencing the expression of muscle-specific genes. Phosphorylation and activation of MEF2, a co-activator of the MRF family member MyoD, was for many years the sole explanation for the promyogenic effect of p38 MAPK. However, it is now clear that the

Acknowledgements

We apologize to the authors whose original work is not included in the references owing to space limitations. Work in the authors' laboratories is supported by the Spanish Ministry of Education and Science (SAF2004–06983, HF2004–0185), the Muscular Dystrophy Association, Marato-TV3 and AFM. E.P. was a recipient of a Novartis postdoctoral fellowship.

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