Editors' ChoicePhysiology

Why Aging Muscles Don't Repair

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Science Signaling  29 Jul 2008:
Vol. 1, Issue 30, pp. ec272
DOI: 10.1126/scisignal.130ec272

As we get older, our muscles don't recover from even minor exercise-induced injury very well. Carlson et al. show that the muscles of young mice have higher Notch signaling than transforming growth factor-β (TGF-β) signaling and that in older mice this is reversed, with TGF-β signaling exceeding that of Notch. TGF-β and the abundance of phosphorylated Smad3 (pSmad3) were increased in aged muscle tissue that was not injured or after injury, compared with that in muscles from young animals. Knockdown of Smad3 in muscles in old mice resulted in enhanced regeneration of the muscle after injury. Further, knockdown of Smad3 resulted in decreased abundance of the cyclin-dependent kinase (CDK) inhibitors p15 and p21, which are encoded by genes regulated by Smad3. A function-blocking antibody against TGF-β also restored muscle repair in old muscles, and exposure of young muscles to recombinant TGF-β led to scarring. Satellite cells (muscle stem cells) isolated from injured muscle were cultured with TGF-β in the presence of conditions that activated Notch, and the TGF-β-mediated increase in CDK inhibitors was decreased by activation of Notch. pSmad3-specific chromatin immunoprecipitation assays in satellite cells exposed to conditions that activate Notch in the presence or absence of TGF-β showed that active Notch and pSmad3 interact at the promoters of the Smad3-regulated genes--p15, p16, p21, and p27. Forced activation of Notch decreased the presence of Smad3 at the target promoters, even in the presence of TGF-β. Thus, Notch appears to directly antagonize Smad3-mediated induction of genes encoding inhibitors of the cell cycle. The loss of this antagonism appears to contribute to the loss of regenerative potential of muscles in older animals.

M. E. Carlson, M. Hsu, I. M. Conboy, Imbalance between pSmad3 and Notch induces CDK inhibitors in old muscle stem cells. Nature 454, 528-532 (2008). [PubMed]

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