Publication Date:
2008-06-17
Description:
Adult skeletal muscle robustly regenerates throughout an organism's life, but as the muscle ages, its ability to repair diminishes and eventually fails. Previous work suggests that the regenerative potential of muscle stem cells (satellite cells) is not triggered in the old muscle because of a decline in Notch activation, and that it can be rejuvenated by forced local activation of Notch. Here we report that, in addition to the loss of Notch activation, old muscle produces excessive transforming growth factor (TGF)-beta (but not myostatin), which induces unusually high levels of TGF-beta pSmad3 in resident satellite cells and interferes with their regenerative capacity. Importantly, endogenous Notch and pSmad3 antagonize each other in the control of satellite-cell proliferation, such that activation of Notch blocks the TGF-beta-dependent upregulation of the cyclin-dependent kinase (CDK) inhibitors p15, p16, p21 and p27, whereas inhibition of Notch induces them. Furthermore, in muscle stem cells, Notch activity determines the binding of pSmad3 to the promoters of these negative regulators of cell-cycle progression. Attenuation of TGF-beta/pSmad3 in old, injured muscle restores regeneration to satellite cells in vivo. Thus a balance between endogenous pSmad3 and active Notch controls the regenerative competence of muscle stem cells, and deregulation of this balance in the old muscle microniche interferes with regeneration.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Carlson, Morgan E -- Hsu, Michael -- Conboy, Irina M -- R01 AG027252/AG/NIA NIH HHS/ -- R21 AG27892/AG/NIA NIH HHS/ -- England -- Nature. 2008 Jul 24;454(7203):528-32. doi: 10.1038/nature07034. Epub 2008 Jun 15.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Bioengineering, University of California, Berkeley, California 94720, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18552838" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Cell Proliferation
;
Coculture Techniques
;
Cyclin-Dependent Kinase Inhibitor Proteins/genetics/*metabolism
;
Male
;
Mice
;
Mice, Inbred C57BL
;
Myoblasts, Skeletal/cytology/drug effects/*metabolism
;
Myostatin
;
Promoter Regions, Genetic/genetics
;
Protein Binding
;
Receptors, Notch/antagonists & inhibitors/*metabolism
;
Satellite Cells, Skeletal Muscle/cytology/drug effects/metabolism
;
Smad3 Protein/genetics/*metabolism
;
Transforming Growth Factor beta/metabolism/pharmacology
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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