Preprint Open Access

FoxO maintains a genuine muscle stem-cell quiescent state until geriatric age

García-Prat, Laura; Perdiguero, Eusebio; Alonso-Martín, Sonia; Dell'Orso, Stefania; Ravichandran, Srikanth; Brooks, Stephen R.; Juan, Aster H.; Campanario, Silvia; Jiang, Kan; Hong, Xiaotong; Ortet, Laura; Ruiz-Bonilla, Vanessa; Flández, Marta; Moiseeva, Victoria; Rebollo, Elena; Jardí, Mercè; Sun, Hong-Wei; Musarò, Antonio; Sandri, Marco; del Sol, Antonio; Sartorelli, Vittorio; Muñoz-Cánoves, Pura

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    <dct:description>&lt;p&gt;&lt;strong&gt;Abstract&lt;/strong&gt;&lt;/p&gt; &lt;p&gt;Tissue regeneration declines with ageing but little is known about whether this arises from changes in stem-cell heterogeneity. Here, in homeostatic skeletal muscle, we identify two quiescent stem-cell states distinguished by relative CD34 expression: CD34High, with stemness properties (genuine state), and CD34Low, committed to myogenic differentiation (primed state). The genuine-quiescent state is unexpectedly preserved into later life, succumbing only in extreme old age due to the acquisition of primed-state traits. Niche-derived IGF1-dependent Akt activation debilitates the genuine stem-cell state by imposing primed-state features via FoxO inhibition. Interventions to neutralize Akt and promote FoxO activity drive a primed-to-genuine state conversion, whereas FoxO inactivation deteriorates the genuine state at a young age, causing regenerative failure of muscle, as occurs in geriatric mice. These findings reveal transcriptional determinants of stem-cell heterogeneity that resist ageing more than previously anticipated and are only lost in extreme old age, with implications for the repair of geriatric muscle.&lt;/p&gt;</dct:description>
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Publication date:
October 26, 2020
DOI:
10.1038/s41556-020-00593-7
Published in:
Nature Cell Biology: 22 pp. 1307-1318.
Grants:
European Commission:
  • Muscle stress relief - Muscle Stress Relief: An integrated research program linking together basic research on secondary myopathies in stress states to innovative translation in applied myology. (645648)
  • UPGRADE - Unlocking Precision Gene Therapy (825825)
  • STEM-AGING - Tissue regeneration and aging: the decisive quiescent stem-cell state (741966)
Communities:
License (for files):
Creative Commons Attribution 4.0 International

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