Research Highlights

Nature Reports Stem Cells
Published online: 19 June 2008 | doi:10.1038/stemcells.2008.96

A metasignalling network makes muscles age

Monya Baker¹

Regeneration is actively repressed in a metasignalling network between TGF-beta and Notch

Old bodies weaken partly because aged muscles are less able to repair themselves. Reporting in Nature, Irina Conboy and colleagues at the University of California, Berkeley finger a new molecular culprit for this phenomenon and show that, at least in skeletal muscle, tissue stem and progenitor cells do not so much lose their ability to repair damage as actively inhibit this potential.

In previous work, Conboy had shown that young satellite cells exposed to old differentiated myofibers are less able to regenerate. These old myofibers secrete factors that increase the activity of a common cell-signalling molecule known as transforming growth factor-beta (TGF-beta), and older satellite cells have elevated levels of phosphorylated Smad3, a transcription factor activated by TGF-beta signalling.

The TGF-beta pathway is not the only one implicated in satellite cell aging. Previous work had shown that loss of the ability to regenerate accompanied the decline of an important signalling pathway known as the Notch pathway. If Notch activity is artificially boosted, old muscle cells become better able to repair themselves after injury.

Conboy's work suggests that either the decline of Notch or the activation of TGF-beta would suffice to explain old muscle's inability to heal. However, the pathways are connected. Notch and TGF-beta pathways exert opposing effects on the activation of proteins that stall a cell's division cycle and are known as cyclin-dependent kinase (CDK) inhibitors. When TGF-beta activates pSmad3, pSMAD3 induces CDK inhibitors and thus prevents satellite cell proliferation.

In contrast, Notch prevents pSmad3 from activating CDK inhibitors, which promotes satellite cell division. Conboy's team established that Notch, Smad3 and RNA polymerase are found together in a complex on promoter regions of several CDK inhibitors, suggesting that Notch physically blocks the effects of pSmad3. Thus, as Notch declines and TGF-beta and pSmad3 rise, the balance between pathways that regulate muscle stem cell proliferation shifts in a way that hinders muscle repair. Knocking down Smad3 expression in vivo downregulated levels of CDK inhibitors in satellite cells residing in old muscle and restored efficient tissue repair.

"They've closed the loop on that pathway," says Mike Rudnicki, who notes that satellite stem cells are a heterogeneous population, so the analysis might miss differences between cells that can self-renew and those destined for differentiation into muscle.

On the other hand, the components in the metasignalling network are ubiquitous in cell regulation. Rudnicki believes this metasignalling network could be "a general mechanism that explains loss of stem cell rigor as we age," he says. "That's a reasonable hypothesis."

Monya Baker is editor of Nature Reports Stem Cells.