Myostatin negatively regulates satellite cell activation and self-renewal

doi:10.1083/jcb.200207056

Published online 8 September 2003. doi:10.1083/jcb.200207056

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© The Rockefeller University Press, 0021-9525/2003/9/1135 $5.00
The Journal of Cell Biology, Volume 162, Number 6, 1135-1147

Article

Myostatin negatively regulates satellite cell activation and self-renewal

Seumas McCroskery¹^,2, Mark Thomas¹, Linda Maxwell², Mridula Sharma¹ and Ravi Kambadur¹

¹ Animal Genomics, AgResearch, Hamilton 2015, New Zealand
² Department of Pathology, University of Auckland, Auckland 1020, New Zealand

Address correspondence to Ravi Kambadur, Animal Genomics, AgResearch, East Street, Hamilton 2015, New Zealand. Tel.: 0064-7-838-5193. Fax: 0064-7-838-5536. email: Ravi.Kambadur{at}agresearch.co.nz

Satellite cells are quiescent muscle stem cells that promotepostnatal muscle growth and repair. Here we show that myostatin,a TGF-ß member, signals satellite cell quiescenceand also negatively regulates satellite cell self-renewal. BrdUlabeling in vivo revealed that, among the Myostatin-deficientsatellite cells, higher numbers of satellite cells are activatedas compared with wild type. In contrast, addition of Myostatinto 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 Cdk2protein in satellite cells. Hence, Myostatin negatively regulatesthe G₁ to S progression and thus maintains the quiescent statusof satellite cells. Immunohistochemical analysis with CD34 antibodiesindicates that there is an increased number of satellite cellsper unit length of freshly isolated Mstn^-/- muscle fibers. Determinationof proliferation rate suggests that this elevation in satellitecell number could be due to increased self-renewal and delayedexpression of the differentiation gene (myogenin) in Mstn^-/-adult myoblasts. Taken together, these results suggest thatMyostatin is a potent negative regulator of satellite cell activationand thus signals the quiescence of satellite cells.

Key Words: myostatin; GDF-8; satellite cell; quiescence; MyoD

M. Sharma and R. Kambadur are co-senior authors.

Abbreviations used in this paper: DM, differentiation medium;E, embryonic day; FM, fiber medium; GM, growth medium.

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