Pax-7 up-regulation inhibits myogenesis and cell cycle progression in satellite cells: a potential mechanism for self-renewal.

Satellite cells are myogenic precursors responsible for skeletal muscle regeneration. Satellite cells are absent in the Pax-7-/- mouse, suggesting that this transcription factor is crucial for satellite cell specification [Seale, P., Sabourin, L.A., Girgis-Gabardo, A., Mansouri, A., Gruss, P., Rudnicki, M.A., 2000. Pax7 is required for the specification of myogenic satellite cells. Cell 102, 777-786]. Analysis of Pax-7 expression in activated satellite cells unexpectedly revealed substantial heterogeneity within individual clones. Further analyses show that Pax-7 and myogenin expression are mutually exclusive during differentiation, where Pax-7 appears to be up-regulated in cells that escape differentiation and exit the cell cycle, suggesting a regulatory relationship between these two transcription factors. Indeed, overexpression of Pax-7 down-regulates MyoD, prevents myogenin induction, and blocks MyoD-induced myogenic conversion of 10T1/2 cells. Overexpression of Pax-7 also promotes cell cycle exit even in proliferation conditions. Together, these results suggest that Pax-7 may play a crucial role in allowing activated satellite cells to reacquire a quiescent, undifferentiated state. These data support the concept that satellite cell self-renewal may be a primary mechanism for replenishment of the satellite cell compartment during skeletal muscle regeneration.

[1]  A. Wernig,et al.  Pax7 distribution in human skeletal muscle biopsies and myogenic tissue cultures , 2004, Cell and Tissue Research.

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

[3]  A. Ciechanover,et al.  Degradation of Myogenic Transcription Factor MyoD by the Ubiquitin Pathway In Vivo and In Vitro: Regulation by Specific DNA Binding , 1998, Molecular and Cellular Biology.

[4]  Helen M. Blau,et al.  Biological Progression from Adult Bone Marrow to Mononucleate Muscle Stem Cell to Multinucleate Muscle Fiber in Response to Injury , 2002, Cell.

[5]  R. Laguens.  Satellite cells of skeletal muscle fibers in human progressive muscular dystrophy , 1963, Virchows Archiv für pathologische Anatomie und Physiologie und für klinische Medizin.

[6]  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.

[7]  Y. Nabeshima,et al.  Cell heterogeneity upon myogenic differentiation: down-regulation of MyoD and Myf-5 generates 'reserve cells'. , 1998, Journal of cell science.

[8]  H. Weintraub,et al.  Expression of a single transfected cDNA converts fibroblasts to myoblasts , 1987, Cell.

[9]  M. Rudnicki,et al.  Pax7 Is Required for the Specification of Myogenic Satellite Cells , 2000, Cell.

[10]  R. E. Allen,et al.  Temporal expression of myogenic regulatory genes during activation, proliferation, and differentiation of rat skeletal muscle satellite cells , 1994, Journal of cellular physiology.

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

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

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

[14]  G. Butler-Browne,et al.  Adult bone marrow-derived stem cells in muscle connective tissue and satellite cell niches. , 2004, The American journal of pathology.

[15]  D. Lockshon,et al.  MyoD binds cooperatively to two sites in a target enhancer sequence: occupancy of two sites is required for activation. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

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

[17]  C. Bader,et al.  Identification of self-renewing myoblasts in the progeny of single human muscle satellite cells. , 1996, Differentiation; research in biological diversity.

[18]  G Cossu,et al.  Muscle regeneration by bone marrow-derived myogenic progenitors. , 1998, Science.

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

[20]  S. Tapscott,et al.  Activation of muscle-specific genes in pigment, nerve, fat, liver, and fibroblast cell lines by forced expression of MyoD. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[21]  D. J. Albright,et al.  Absence of exogenous satellite cell contribution to regeneration of frozen skeletal muscle , 1986, Journal of Muscle Research & Cell Motility.

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

[23]  K. Barald,et al.  Fusion between myoblasts and adult muscle fibers promotes remodeling of fibers into myotubes in vitro. , 1990, Development.

[24]  D. Watt,et al.  Muscle stem cells , 2002, The Journal of pathology.

[25]  A. Mauro.  SATELLITE CELL OF SKELETAL MUSCLE FIBERS , 1961, The Journal of biophysical and biochemical cytology.

[26]  M. Rudnicki,et al.  Pax7 Is Necessary and Sufficient for the Myogenic Specification of CD45+:Sca1+ Stem Cells from Injured Muscle , 2004, PLoS biology.