Regeneration of skeletal muscle depends on a population of adult stem cells (satellite cells) that remain quiescent throughout life. Satellite cell regenerative functions decline with ageing. Here we report that geriatric satellite cells are incapable of maintaining their normal quiescent state in muscle homeostatic conditions, and that this irreversibly affects their intrinsic regenerative and self-renewal capacities. In geriatric mice, resting satellite cells lose reversible quiescence by switching to an irreversible pre-senescence state, caused by derepression of p16(INK4a) (also called Cdkn2a). On injury, these cells fail to activate and expand, undergoing accelerated entry into a full senescence state (geroconversion), even in a youthful environment. p16(INK4a) silencing in geriatric satellite cells restores quiescence and muscle regenerative functions. Our results demonstrate that maintenance of quiescence in adult life depends on the active repression of senescence pathways. As p16(INK4a) is dysregulated in human geriatric satellite cells, these findings provide the basis for stem-cell rejuvenation in sarcopenic muscles.
Snail1 and Zeb1 are E-cadherin-transcriptional repressors induced during epithelial mesenchymal transition (EMT).In this article we have analyzed the factors controlling Zeb1 expression during EMT. In NMuMG cells treated with TGF-, Snail1 RNA and protein are induced 1 h after addition of the cytokine preceding Zeb1 up-regulation that requires 6 -8 h. Zeb1 gene expression is caused by increased RNA levels but also by enhanced protein stability and is markedly dependent on Snail1 because depletion of this protein prevents Zeb1 protein and RNA up-regulation. In addition to Snail1, depletion of the Twist transcriptional factor retards Zeb1 stimulation by TGF- or decreases Zeb1 expression in other cellular models indicating that this factor is also required for Zeb1 expression. Accordingly, Snail1 and Twist cooperate in the induction of Zeb1: cotransfection of both cDNAs is required for the maximal expression of ZEB1 mRNA. Unexpectedly, the expression of Snail1 and Twist shows a mutual dependence although to a different extent; whereas Twist depletion retards Snail1 up-regulation by TGF-, Snail1 is necessary for the rapid increase in Twist protein and later up-regulation of Twist1 mRNA induced by the cytokine. Besides this effect on Twist, Snail1 also induces the nuclear translocation of Ets1, another factor required for Zeb1 expression. Both Twist and Ets1 bind to the ZEB1 promoter although to different elements: whereas Ets1 interacts with the proximal promoter, Twist does it with a 700-bp sequence upstream of the transcription start site. These results indicate that Snail1 controls Zeb1 expression at multiple levels and acts cooperatively with Twist in the ZEB1 gene transcription induction. Epithelial to mesenchymal transition (EMT)5 defines a process during which cells lose their epithelial characteristics and acquire typical properties of mesenchymal cells. This transition requires complex changes in cell shape that happen concomitantly to gene expression reprogramming (1). The main hallmark of EMT is the down-regulation of the adherens junction protein E-cadherin due to transcriptional repression. Overexpression of Snail1 in epithelial cells causes a complete EMT and down-regulates E-cadherin through its binding to the Ecadherin promoter (2, 3); moreover, up-regulation of Snail1 RNA is observed in many cellular systems when EMT is induced (4). Besides Snail1, other cellular factors such as the Snail1-related Slug (Snail2) (5), the basic helix-loop-helix protein E12/E47 (6), or two members of the Zeb family, Zeb1/ ␦EF-1 and Zeb2/Sip1 (7-9), are capable of repressing E-cadherin (CDH1) promoter activity and RNA levels. Curiously, all of these factors bind to the same elements in the CDH1 gene: three E-boxes with a core 5Ј-CACCTG-3Ј sequence placed in the proximal promoter. Different results indicate that expression of some of these genes is interdependent; for instance, it has been shown that overexpression of Snail1 increases the levels of ZEB1 mRNA (10). A relevant role for Zeb1 in the definitive repression o...
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