FoxO maintains a genuine muscle stem-cell quiescent state until geriatric age
Creators
- García-Prat, Laura1
- Perdiguero, Eusebio2
- Alonso-Martín, Sonia3
- Dell'Orso, Stefania4
- Ravichandran, Srikanth5
- Brooks, Stephen R.6
- Juan, Aster H.4
- Campanario, Silvia7
- Jiang, Kan6
- Hong, Xiaotong8
- Ortet, Laura2
- Ruiz-Bonilla, Vanessa2
- Flández, Marta9
- Moiseeva, Victoria2
- Rebollo, Elena10
- Jardí, Mercè2
- Sun, Hong-Wei6
- Musarò, Antonio11
- Sandri, Marco12
- del Sol, Antonio13
- Sartorelli, Vittorio4
- Muñoz-Cánoves, Pura14
- 1. Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada - Department of Experimental and Health Sciences, Pompeu Fabra University (UPF), CIBER on Neurodegenerative Diseases (CIBERNED), Barcelona, Spain - Spanish National Center on Cardiovascular Research (CNIC), Madrid, Spain
- 2. Department of Experimental and Health Sciences, Pompeu Fabra University (UPF), CIBER on Neurodegenerative Diseases (CIBERNED), Barcelona, Spain
- 3. Neurosciences Area, Biodonostia Health Research Institute, Donostia-San Sebastián, San Sebastián, Spain - Spanish National Center on Cardiovascular Research (CNIC), Madrid, Spain
- 4. Laboratory of Muscle Stem Cells and Gene Regulation, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), NIH Bethesda, Bethesda, MD, USA
- 5. Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg
- 6. Biodata Mining and Discovery Section, NIAMS, NIH Bethesda, Bethesda, MD, USA
- 7. Department of Experimental and Health Sciences, Pompeu Fabra University (UPF), CIBER on Neurodegenerative Diseases (CIBERNED), Barcelona, Spain - Spanish National Center on Cardiovascular Research (CNIC), Madrid, Spain
- 8. Spanish National Center on Cardiovascular Research (CNIC), Madrid, Spain
- 9. Grupo de Investigación en Oncología Clínico Traslacional, Instituto de Investigación Hospital 12 de Octubre, Madrid, Spain - Spanish National Center on Cardiovascular Research (CNIC), Madrid, Spain
- 10. Molecular Imaging Platform, Molecular Biology Institute of Barcelona (IBMB-CSIC), Barcelona, Spain
- 11. DAHFMO-Unit of Histology and Medical Embryology, Laboratory Affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Sapienza University of Rome, Rome, Italy
- 12. Department of Biomedical Science, University of Padova, Padova, Italy
- 13. Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg - CIC bioGUNE, Derio, Spain - IKERBASQUE, Basque Foundation for Science, Bilbao, Spain
- 14. Department of Experimental and Health Sciences, Pompeu Fabra University (UPF), CIBER on Neurodegenerative Diseases (CIBERNED), Barcelona, Spain - Spanish National Center on Cardiovascular Research (CNIC), Madrid, Spain - ICREA, Barcelona, Spain
Description
Abstract
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.
Files
Garcia-Prat 2021 Preprint.pdf
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Additional details
Funding
- 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
- European Commission
- UPGRADE – Unlocking Precision Gene Therapy 825825
- European Commission
- STEM-AGING – Tissue regeneration and aging: the decisive quiescent stem-cell state 741966
- European Commission