The p38α/β MAPK functions as a molecular switch to activate the quiescent satellite cell

Somatic stem cells cycle slowly or remain quiescent until required for tissue repair and maintenance. Upon muscle injury, stem cells that lie between the muscle fiber and basal lamina (satellite cells) are activated, proliferate, and eventually differentiate to repair the damaged muscle. Satellite cells in healthy muscle are quiescent, do not express MyoD family transcription factors or cell cycle regulatory genes and are insulated from the surrounding environment. Here, we report that the p38α/β family of mitogen-activated protein kinases (MAPKs) reversibly regulates the quiescent state of the skeletal muscle satellite cell. Inhibition of p38α/β MAPKs (a) promotes exit from the cell cycle, (b) prevents differentiation, and (c) insulates the cell from most external stimuli allowing the satellite cell to maintain a quiescent state. Activation of satellite cells and p38α/β MAPKs occurs concomitantly, providing further support that these MAPKs function as a molecular switch for satellite cell activation.

[1]  H. Rauvala,et al.  Essential and separable roles for Syndecan-3 and Syndecan-4 in skeletal muscle development and regeneration. , 2004, Genes & development.

[2]  J. Boehm,et al.  p38 MAP kinases: key signalling molecules as therapeutic targets for inflammatory diseases , 2003, Nature Reviews Drug Discovery.

[3]  Yi-Ping Li.  TNF-α is a mitogen in skeletal muscle , 2003 .

[4]  T. Underhill,et al.  Inhibition of p38 MAPK signaling promotes late stages of myogenesis , 2003, Journal of Cell Science.

[5]  K. Storey,et al.  Mitogen-activated protein kinases: new signaling pathways functioning in cellular responses to environmental stress , 2003, Journal of Experimental Biology.

[6]  A. Hattori,et al.  Release of hepatocyte growth factor from mechanically stretched skeletal muscle satellite cells and role of pH and nitric oxide. , 2002, Molecular biology of the cell.

[7]  Qing Xu,et al.  p38 Mitogen-activated protein kinase-, calcium-calmodulin-dependent protein kinase-, and calcineurin-mediated signaling pathways transcriptionally regulate myogenin expression. , 2002, Molecular biology of the cell.

[8]  G. Merlino,et al.  Hepatocyte growth factor/scatter factor activates proliferation in melanoma cells through p38 MAPK, ATF-2 and cyclin D1 , 2002, Oncogene.

[9]  N. Jones,et al.  Atypical Protein Kinase Cs Are the Ras Effectors That Mediate Repression of Myogenic Satellite Cell Differentiation , 2002, Molecular and Cellular Biology.

[10]  B. Olwin,et al.  Syndecan-3 and syndecan-4 specifically mark skeletal muscle satellite cells and are implicated in satellite cell maintenance and muscle regeneration. , 2001, Developmental biology.

[11]  M. Rudnicki,et al.  The potential of muscle stem cells. , 2001, Developmental cell.

[12]  H. Westerblad,et al.  Effects of concentric and eccentric contractions on phosphorylation of MAPKerk1/2 and MAPKp38 in isolated rat skeletal muscle , 2001, The Journal of physiology.

[13]  T. Hawke,et al.  Myogenic satellite cells: physiology to molecular biology. , 2001, Journal of applied physiology.

[14]  N. Jones,et al.  ERK1/2 is required for myoblast proliferation but is dispensable for muscle gene expression and cell fusion , 2001, Journal of cellular physiology.

[15]  B. Wold,et al.  MyoD(-/-) satellite cells in single-fiber culture are differentiation defective and MRF4 deficient. , 2000, Developmental biology.

[16]  Zhenguo Wu,et al.  p38 and Extracellular Signal-Regulated Kinases Regulate the Myogenic Program at Multiple Steps , 2000, Molecular and Cellular Biology.

[17]  Jiahuai Han,et al.  Induction of terminal differentiation by constitutive activation of p38 MAP kinase in human rhabdomyosarcoma cells. , 2000, Genes & development.

[18]  M. Rudnicki,et al.  A new look at the origin, function, and "stem-cell" status of muscle satellite cells. , 2000, Developmental biology.

[19]  B. Olwin,et al.  Loss of FGF receptor 1 signaling reduces skeletal muscle mass and disrupts myofiber organization in the developing limb. , 2000, Developmental biology.

[20]  M. Kohno,et al.  Specific Activation of the p38 Mitogen-activated Protein Kinase Signaling Pathway and Induction of Neurite Outgrowth in PC12 Cells by Bone Morphogenetic Protein-2* , 1999, The Journal of Biological Chemistry.

[21]  Jeffrey L. Wrana,et al.  Post-translational control of the MEF2A transcriptional regulatory protein , 1999, Nucleic Acids Res..

[22]  P. Maher,et al.  p38 Mitogen-activated Protein Kinase Activation Is Required for Fibroblast Growth Factor-2-stimulated Cell Proliferation but Not Differentiation* , 1999, The Journal of Biological Chemistry.

[23]  Andrew D. Sharrocks,et al.  Targeting of p38 Mitogen-Activated Protein Kinases to MEF2 Transcription Factors , 1999, Molecular and Cellular Biology.

[24]  Philip R. Cohen,et al.  Use of a drug‐resistant mutant of stress‐activated protein kinase 2a/p38 to validate the in vivo specificity of SB 203580 , 1999, FEBS letters.

[25]  E. Bengal,et al.  p38 Mitogen-activated Protein Kinase Pathway Promotes Skeletal Muscle Differentiation , 1999, The Journal of Biological Chemistry.

[26]  P. Cohen,et al.  Stress-activated Protein Kinase-2/p38 and a Rapamycin-sensitive Pathway Are Required for C2C12 Myogenesis* , 1999, The Journal of Biological Chemistry.

[27]  Yu. Fedorov,et al.  Regulation of Myogenesis by Fibroblast Growth Factors Requires Beta-Gamma Subunits of Pertussis Toxin-Sensitive G Proteins , 1998, Molecular and Cellular Biology.

[28]  E. Nishida,et al.  Requirement of p38 Mitogen-activated Protein Kinase for Neuronal Differentiation in PC12 Cells* , 1998, The Journal of Biological Chemistry.

[29]  Ozerniuk Nd.  Regulation of myogenesis , 1998 .

[30]  S. Tapscott,et al.  Mitogen-activated Protein Kinase Pathway Is Involved in the Differentiation of Muscle Cells* , 1998, The Journal of Biological Chemistry.

[31]  A. Roulston,et al.  Early Activation of c-Jun N-terminal Kinase and p38 Kinase Regulate Cell Survival in Response to Tumor Necrosis Factor α* , 1998, The Journal of Biological Chemistry.

[32]  O. Halevy,et al.  HGF/SF is present in normal adult skeletal muscle and is capable of activating satellite cells. , 1998, Developmental biology.

[33]  M. Cobb,et al.  MEKK1 Binds Directly to the c-Jun N-terminal Kinases/Stress-activated Protein Kinases* , 1997, The Journal of Biological Chemistry.

[34]  B. Wold,et al.  Single-cell analysis of regulatory gene expression in quiescent and activated mouse skeletal muscle satellite cells. , 1997, Developmental biology.

[35]  N. Tonks,et al.  Regulation of distinct stages of skeletal muscle differentiation by mitogen-activated protein kinases. , 1997, Science.

[36]  J. Florini,et al.  The Mitogenic and Myogenic Actions of Insulin-like Growth Factors Utilize Distinct Signaling Pathways* , 1997, The Journal of Biological Chemistry.

[37]  A. Wolfman,et al.  Distinct signaling pathways regulate transformation and inhibition of skeletal muscle differentiation by oncogenic Ras , 1997, Oncogene.

[38]  M. Lotz,et al.  Selective activation of the mitogen-activated protein kinase subgroups c-Jun NH2 terminal kinase and p38 by IL-1 and TNF in human articular chondrocytes. , 1996, The Journal of clinical investigation.

[39]  M. R. Calera,et al.  Stimulation of C2C12 myoblast growth by basic fibroblast growth factor and insulin-like growth factor 1 can occur via mitogen-activated protein kinase-dependent and -independent pathways , 1996, Molecular and cellular biology.

[40]  E. Schultz.  Satellite cell proliferative compartments in growing skeletal muscles. , 1996, Developmental biology.

[41]  B. Olwin,et al.  A requirement for fibroblast growth factor in regulation of skeletal muscle growth and differentiation cannot be replaced by activation of platelet-derived growth factor signaling pathways , 1995, Molecular and cellular biology.

[42]  E. Krebs,et al.  Differential activation of mitogen-activated protein kinase in response to basic fibroblast growth factor in skeletal muscle cells. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[43]  Z. Yablonka-Reuveni,et al.  Temporal expression of regulatory and structural muscle proteins during myogenesis of satellite cells on isolated adult rat fibers. , 1994, Developmental biology.

[44]  G. Lyons,et al.  MyoD, myogenin independent differentiation of primordial myoblasts in mouse somites , 1992, The Journal of cell biology.

[45]  C. Clegg,et al.  Growth factor control of skeletal muscle differentiation: commitment to terminal differentiation occurs in G1 phase and is repressed by fibroblast growth factor , 1987, The Journal of cell biology.

[46]  P. Chomczyński,et al.  Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. , 1987, Analytical biochemistry.

[47]  R. Bischoff.  Proliferation of muscle satellite cells on intact myofibers in culture. , 1986, Developmental biology.

[48]  E. Schultz,et al.  Effects of skeletal muscle regeneration on the proliferation potential of satellite cells , 1985, Mechanisms of Ageing and Development.

[49]  E. Schultz,et al.  Satellite cells are mitotically quiescent in mature mouse muscle: an EM and radioautographic study. , 1978, The Journal of experimental zoology.

[50]  Yi-Ping Li.  TNF-alpha is a mitogen in skeletal muscle. , 2003, American journal of physiology. Cell physiology.

[51]  P. Cohen,et al.  Specificity and mechanism of action of some commonly used protein kinase inhibitors. , 2000, The Biochemical journal.

[52]  N. Ahn,et al.  Signal transduction through MAP kinase cascades. , 1998, Advances in cancer research.

[53]  N. D. Ozerniuk.  [Regulation of myogenesis]. , 1998, Izvestiia Akademii nauk. Seriia biologicheskaia.

[54]  E. Schultz,et al.  Skeletal muscle satellite cells. , 1994, Reviews of physiology, biochemistry and pharmacology.