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PMID: 12963705 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Myostatin negatively regulates satellite cell activation and self-renewal.

The Journal of cell biology ·Vol. 162 ·No. 6 ·2003-09-15 ·Pages 1135-47

McCroskery S, Thomas M, Maxwell L, Sharma M, Kambadur R

Abstract

Satellite cells are quiescent muscle stem cells that promote postnatal muscle growth and repair. Here we show that myostatin, a TGF-beta member, signals satellite cell quiescence and also negatively regulates satellite cell self-renewal. BrdU labeling in vivo revealed that, among the Myostatin-deficient satellite cells, higher numbers of satellite cells are activated as compared with wild type. In contrast, addition of Myostatin to myofiber explant cultures inhibits satellite cell activation. Cell cycle analysis confirms that Myostatin up-regulated p21, a Cdk inhibitor, and decreased the levels and activity of Cdk2 protein in satellite cells. Hence, Myostatin negatively regulates the G1 to S progression and thus maintains the quiescent status of satellite cells. Immunohistochemical analysis with CD34 antibodies indicates that there is an increased number of satellite cells per unit length of freshly isolated Mstn-/- muscle fibers. Determination of proliferation rate suggests that this elevation in satellite cell number could be due to increased self-renewal and delayed expression of the differentiation gene (myogenin) in Mstn-/- adult myoblasts. Taken together, these results suggest that Myostatin is a potent negative regulator of satellite cell activation and thus signals the quiescence of satellite cells.

MeSH Terms
Animals Antigens, CD34/metabolism CDC2-CDC28 Kinases Cell Differentiation/physiology Cell Division/physiology Cyclin-Dependent Kinase 2 Cyclin-Dependent Kinase Inhibitor p21 Cyclin-Dependent Kinases/metabolism Cyclins/metabolism Down-Regulation/physiology Feedback, Physiological/genetics G1 Phase/genetics Gene Expression Regulation, Developmental/genetics Mice Mice, Knockout Muscle Fibers, Skeletal/cytology,metabolism Muscle, Skeletal/cytology,growth & development,metabolism Myoblasts/cytology,metabolism Myogenin/genetics,metabolism Myostatin Protein Serine-Threonine Kinases/metabolism Regeneration/physiology S Phase/genetics Satellite Cells, Skeletal Muscle/cytology,metabolism Transforming Growth Factor beta/deficiency,genetics,metabolism Up-Regulation/physiology
Chemicals
Antigens, CD34 Cdkn1a protein, mouse Cyclin-Dependent Kinase Inhibitor p21 Cyclins Mstn protein, mouse Myog protein, mouse Myogenin Myostatin Transforming Growth Factor beta Protein Serine-Threonine Kinases CDC2-CDC28 Kinases Cdk2 protein, mouse Cyclin-Dependent Kinase 2 Cyclin-Dependent Kinases
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
McCroskery Seumas
Animal Genomics, AgResearch, Hamilton 2015, New Zealand.
Thomas Mark
Maxwell Linda
Sharma Mridula
Kambadur Ravi
References (43)
43 references, click to expand
  1. Loss of FGF receptor 1 signaling reduces skeletal muscle mass and disrupts myofiber organization in the developing limb.
    Dev Biol. 2000 Feb 1;218(1):21-37 PMID: 10644408
  2. Skeletal muscle myostatin mRNA expression is fiber-type specific and increases during hindlimb unloading.
    Am J Physiol. 1999 Aug;277(2 Pt 2):R601-6 PMID: 10444569
  3. Modulation of myostatin expression during modified muscle use.
    FASEB J. 2000 Jan;14(1):103-10 PMID: 10627285
  4. Dynamics of nuclei of muscle fibers and connective tissue cells in normal and denervated rat muscles.
    Muscle Nerve. 2000 Apr;23(4):617-26 PMID: 10716774
  5. Dominant negative myostatin produces hypertrophy without hyperplasia in muscle.
    FEBS Lett. 2000 May 26;474(1):71-5 PMID: 10828454
  6. Myostatin regulation during skeletal muscle regeneration.
    J Cell Physiol. 2000 Sep;184(3):356-63 PMID: 10911367
  7. MyoD(-/-) satellite cells in single-fiber culture are differentiation defective and MRF4 deficient.
    Dev Biol. 2000 Aug 15;224(2):122-37 PMID: 10926754
  8. Pax7 is required for the specification of myogenic satellite cells.
    Cell. 2000 Sep 15;102(6):777-86 PMID: 11030621
  9. Insulin-like growth factor-I extends in vitro replicative life span of skeletal muscle satellite cells by enhancing G1/S cell cycle progression via the activation of phosphatidylinositol 3'-kinase/Akt signaling pathway.
    J Biol Chem. 2000 Nov 17;275(46):35942-52 PMID: 10962000
  10. Myostatin, a negative regulator of muscle growth, functions by inhibiting myoblast proliferation.
    J Biol Chem. 2000 Dec 22;275(51):40235-43 PMID: 10976104
  11. Expression of CD34 and Myf5 defines the majority of quiescent adult skeletal muscle satellite cells.
    J Cell Biol. 2000 Dec 11;151(6):1221-34 PMID: 11121437
  12. Resistance exercise decreases skeletal muscle tumor necrosis factor alpha in frail elderly humans.
    FASEB J. 2001 Feb;15(2):475-82 PMID: 11156963
  13. Myostatin inhibits cell proliferation and protein synthesis in C2C12 muscle cells.
    Am J Physiol Endocrinol Metab. 2001 Feb;280(2):E221-8 PMID: 11158924
  14. Transplanted primary neonatal myoblasts can give rise to functional satellite cells as identified using the Myf5nlacZl+ mouse.
    Gene Ther. 2001 May;8(10):778-83 PMID: 11420641
  15. Suppression of body fat accumulation in myostatin-deficient mice.
    J Clin Invest. 2002 Mar;109(5):595-601 PMID: 11877467
  16. Satellite cell proliferation and differentiation during postnatal growth of porcine skeletal muscle.
    Am J Physiol Cell Physiol. 2002 Apr;282(4):C899-906 PMID: 11880278
  17. Myostatin is an inhibitor of myogenic differentiation.
    Am J Physiol Cell Physiol. 2002 May;282(5):C993-9 PMID: 11940514
  18. Loss of myostatin attenuates severity of muscular dystrophy in mdx mice.
    Ann Neurol. 2002 Dec;52(6):832-6 PMID: 12447939
  19. Functional improvement of dystrophic muscle by myostatin blockade.
    Nature. 2002 Nov 28;420(6914):418-21 PMID: 12459784
  20. Myostatin inhibits myoblast differentiation by down-regulating MyoD expression.
    J Biol Chem. 2002 Dec 20;277(51):49831-40 PMID: 12244043
  21. Inhibition of myostatin in adult mice increases skeletal muscle mass and strength.
    Biochem Biophys Res Commun. 2003 Jan 24;300(4):965-71 PMID: 12559968
  22. Absence of p21CIP rescues myogenic progenitor cell proliferative and regenerative capacity in Foxk1 null mice.
    J Biol Chem. 2003 Feb 7;278(6):4015-20 PMID: 12446708
  23. Mechanisms involved in the inhibition of myoblast proliferation and differentiation by myostatin.
    Exp Cell Res. 2003 Jun 10;286(2):263-75 PMID: 12749855
  24. A rapid and convenient assay for counting cells cultured in microwell plates: application for assessment of growth factors.
    J Cell Sci. 1989 Mar;92 ( Pt 3):513-8 PMID: 2592453
  25. Analysis of muscle regeneration using single myofibers in culture.
    Med Sci Sports Exerc. 1989 Oct;21(5 Suppl):S164-72 PMID: 2607951
  26. In vitro and in vivo expression of alpha 7 integrin and desmin define the primary and secondary myogenic lineages.
    Dev Biol. 1993 Mar;156(1):209-29 PMID: 8449367
  27. Molecular and cell biology of skeletal muscle regeneration.
    Mol Cell Biol Hum Dis Ser. 1993;3:210-56 PMID: 8111541
  28. Culturing satellite cells from living single muscle fiber explants.
    In Vitro Cell Dev Biol Anim. 1995 Nov;31(10):773-9 PMID: 8564066
  29. Isolation and functional properties of murine hematopoietic stem cells that are replicating in vivo.
    J Exp Med. 1996 Apr 1;183(4):1797-806 PMID: 8666936
  30. Uncoupling of Grb2 from the Met receptor in vivo reveals complex roles in muscle development.
    Cell. 1996 Nov 1;87(3):531-42 PMID: 8898205
  31. Phenotype of adult mouse muscle myoblasts reflects their fiber type of origin.
    Differentiation. 1996 Mar;60(1):39-45 PMID: 8935927
  32. Regulation of skeletal muscle mass in mice by a new TGF-beta superfamily member.
    Nature. 1997 May 1;387(6628):83-90 PMID: 9139826
  33. Tissue culture of skeletal muscle.
    Methods Mol Biol. 1997;75:131-44 PMID: 9276265
  34. Mutations in myostatin (GDF8) in double-muscled Belgian Blue and Piedmontese cattle.
    Genome Res. 1997 Sep;7(9):910-6 PMID: 9314496
  35. Double muscling in cattle due to mutations in the myostatin gene.
    Proc Natl Acad Sci U S A. 1997 Nov 11;94(23):12457-61 PMID: 9356471
  36. Skeletal muscle satellite cell cultures.
    Methods Cell Biol. 1997;52:155-76 PMID: 9379949
  37. Single-cell analysis of regulatory gene expression in quiescent and activated mouse skeletal muscle satellite cells.
    Dev Biol. 1997 Nov 15;191(2):270-83 PMID: 9398440
  38. Cell heterogeneity upon myogenic differentiation: down-regulation of MyoD and Myf-5 generates 'reserve cells'.
    J Cell Sci. 1998 Mar;111 ( Pt 6):769-79 PMID: 9472005
  39. The muscle regulatory factors MyoD and myf-5 undergo distinct cell cycle-specific expression in muscle cells.
    J Cell Biol. 1998 Sep 21;142(6):1447-59 PMID: 9744876
  40. Organization of the human myostatin gene and expression in healthy men and HIV-infected men with muscle wasting.
    Proc Natl Acad Sci U S A. 1998 Dec 8;95(25):14938-43 PMID: 9843994
  41. The transition from proliferation to differentiation is delayed in satellite cells from mice lacking MyoD.
    Dev Biol. 1999 Jun 15;210(2):440-55 PMID: 10357902
  42. Myostatin, a transforming growth factor-beta superfamily member, is expressed in heart muscle and is upregulated in cardiomyocytes after infarct.
    J Cell Physiol. 1999 Jul;180(1):1-9 PMID: 10362012
  43. A new look at the origin, function, and "stem-cell" status of muscle satellite cells.
    Dev Biol. 2000 Feb 15;218(2):115-24 PMID: 10656756
Article Info
Journal
The Journal of cell biology
Abbr.
J Cell Biol
ISSN
0021-9525
DOI
10.1083/jcb.200207056
Published
2003-09-15
Epub
2003-00-08
Pages
1135-47
Language
English
Region
United States
NLM ID
0375356
PMCID
PMC2172861
Subset
IM
External Links
PubMed source DOI: 10.1083/jcb.200207056 PMC Full Text View journal details
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