Published 17 July 2006. doi:10.1083/jcb.200605028
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 174, Number 2, 245-253
Entry of muscle satellite cells into the cell cycle requires sphingolipid signaling
Yosuke Nagata1,
Terence A. Partridge2,
Ryoichi Matsuda1, and
Peter S. Zammit3
1 Department of Life Sciences, The University of Tokyo, Meguro-ku, Tokyo 153-8902, Japan
2 Children's National Medical Center, Washington, DC 20010
3 Randall Division of Cell and Molecular Biophysics, King's College London, London SE1 1UL, England, UK
Correspondence to Peter S. Zammit: peter.zammit{at}kcl.ac.uk
Adult skeletal muscle is able to repeatedly regenerate because of the presence of satellite cells, a population of stem cells resident beneath the basal lamina that surrounds each myofiber. Little is known, however, of the signaling pathways involved in the activation of satellite cells from quiescence to proliferation, a crucial step in muscle regeneration. We show that sphingosine-1-phosphate induces satellite cells to enter the cell cycle. Indeed, inhibiting the sphingolipid-signaling cascade that generates sphingosine-1-phosphate significantly reduces the number of satellite cells able to proliferate in response to mitogen stimulation in vitro and perturbs muscle regeneration in vivo. In addition, metabolism of sphingomyelin located in the inner leaflet of the plasma membrane is probably the main source of sphingosine-1-phosphate used to mediate the mitogenic signal. Together, our observations show that sphingolipid signaling is involved in the induction of proliferation in an adult stem cell and a key component of muscle regeneration.
Abbreviations used in this paper: bSMase, bacterial sphingomyelinase; CFCS, charcoal-stripped FCS; DMS, N,N-dimethylsphingosine; eMyHC, embryonic myosin heavy chain; FB1, fumonisin B1; HGF, hepatocyte growth factor; N-SMase, neutral sphingomyelinase; PCNA, proliferating cell nuclear antigen; S1P, sphingosine-1-phosphate; TA, tibialis anterior.

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