The aged niche disrupts muscle stem cell quiescence
Open accessAbstract
The niche is a conserved regulator of stem cell quiescence and function. During ageing, stem cell function declines. To what extent and by what means age-related changes within the niche contribute to this phenomenon are unknown. Here we demonstrate that the aged muscle stem cell niche, the muscle fibre, expresses Fgf2 under homeostatic conditions, driving a subset of satellite cells to break quiescence and lose their self-renewing capacity. We show in mice that relatively dormant aged satellite cells robustly express sprouty 1 (Spry1), an inhibitor of fibroblast growth factor (FGF) signalling. Increasing FGF signalling in aged satellite cells under homeostatic conditions by removing Spry1 results in the loss of quiescence, satellite cell depletion and diminished regenerative capacity. Conversely, reducing niche-derived FGF activity through inhibition of Fgfr1 signalling or overexpression of Spry1 in satellite cells prevents their depletion. These experiments identify an age-dependent change in the stem cell niche that directly influences stem cell quiescence and function.
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In aged muscle, stronger FGF2 signaling in the stem cell niche causes satellite cells to leave quiescence and impairs muscle regeneration.
“In a similar vein, increased fibroblast growth factor 2 (FGF2) signaling in the aged muscle stem cell niche also drives loss of quiescence in satellite cells, leading to impaired muscle regenerative capacity132.”
From Stem cell aging: mechanisms, regulators and therapeutic opportunities (2014) · cites this paper as [132]
These two changes help explain why satellite cells become less responsive in older animals.
“Both of these alterations contribute to acquired loss of satellite cell responsiveness in older animals.”
From Stem cell aging: mechanisms, regulators and therapeutic opportunities (2014) · cites this paper as [132]
Advancing age is associated with loss of skeletal muscle regenerative potential.
“Advancing age is associated with a loss of regenerative potential.”
From Skeletal muscle aging, cellular senescence, and senotherapeutics: current knowledge and future directions (2021) · cites this paper as Chakkalakal et al., 2012
The age-related loss of regenerative potential is partly due to reduced satellite cell content in old mice and humans but primarily driven by impaired activation and proliferation in response to damage-inducing stimuli.
“This is partly due to reduced satellite cell content in old mice (20–24-months) (Brack et al., 2007; Chakkalakal et al., 2012) and humans (Carlson et al., 2009) but is primarily driven by impaired activation and proliferation in response to damage-inducing stimuli.”
From Skeletal muscle aging, cellular senescence, and senotherapeutics: current knowledge and future directions (2021) · cites this paper as Chakkalakal et al., 2012
Other stem cell subpopulations lose quiescence and become abnormally activated, particularly in blood and muscle.
“Other stem cell subpopulations lose quiescence and become abnormally activated, particularly in blood and muscle12,35,44.”
From Ageing and rejuvenation of tissue stem cells and their niches (2023) · cites this paper as [35]
During ageing, skeletal myofibres start secreting factors such as FGF2, which induce MuSC activation and ultimately decrease their self-renewing properties.
“During ageing, skeletal myofibres start secreting other factors, such as FGF2, which induce MuSC activation and ultimately decrease their self-renewing properties35.”
From Ageing and rejuvenation of tissue stem cells and their niches (2023) · cites this paper as [35]
Differences in regenerative potential between stem cells are traditionally viewed as the result of differences in the characteristics of stable cell phenotypes.
“These differences in regenerative potential between stem cells are traditionally viewed as the result of differences in the characteristics of stable cell phenotypes (Altschuler and Wu, 2010; Blau et al., 2015; Chakkalakal et al., 2012).”
From Aging induces aberrant state transition kinetics in murine muscle stem cells (2020) · cites this paper as Chakkalakal et al., 2012
LRCs, which undergo fewer divisions during development, are more regenerative than nonLRCs, which undergo many divisions.
“We previously showed that LRCs, which undergo fewer divisions during development, are more regenerative than nonLRCs, which undergo many divisions (Chakkalakal et al., 2012; Chakkalakal et al., 2014).”
From Aging induces aberrant state transition kinetics in murine muscle stem cells (2020) · cites this paper as Chakkalakal et al., 2012
LRCs and nonLRCs are discrete populations of MuSCs with different proliferative histories and different regenerative potentials.
“We previously described LRCs and nonLRCs as discrete populations of MuSCs with different proliferative histories and different regenerative potentials (Chakkalakal et al., 2012, 2014).”
From Aging induces aberrant state transition kinetics in murine muscle stem cells (2020) · cites this paper as Chakkalakal et al., 2012
LRCs are functionally distinct from nonLRCs, and this functional difference persists throughout life.
“LRCs are functionally distinct from nonLRCs, and this functional difference persists throughout life (Chakkalakal et al., 2012, 2014).”
From Aging induces aberrant state transition kinetics in murine muscle stem cells (2020) · cites this paper as Chakkalakal et al., 2012
The conversion of highly regenerative LRCs to less regenerative nonLRCs is a factor in this regenerative decline.
“We previously found that the conversion of highly regenerative LRCs to less regenerative nonLRCs is a factor in this regenerative decline (Chakkalakal et al., 2012, 2014).”
From Aging induces aberrant state transition kinetics in murine muscle stem cells (2020) · cites this paper as Chakkalakal et al., 2012
LRCs are believed to be 'reserve' stem cells, whereas nonLRCs are presumed to be precocious in their response based on differentiation assays.
“This result is surprising, as LRCs are believed to be ‘reserve’ stem cells, whereas nonLRCs are presumed to be precocious in their response based on differentiation assays (Chakkalakal et al., 2012, 2014).”
From Aging induces aberrant state transition kinetics in murine muscle stem cells (2020) · cites this paper as Chakkalakal et al., 2012
LRCs express higher levels of Pax7.
“LRCs express higher levels of Pax7 (Chakkalakal et al., 2012), such that rapid activation of LRCs might give rise to a population structure that present non-monotonic changes in Pax7 when averaging across all cells at a given activation state.”
From Aging induces aberrant state transition kinetics in murine muscle stem cells (2020) · cites this paper as Chakkalakal et al., 2012
There are dramatic differences in functional potential between aged and young cell populations.
“The lack of unique aged transcriptional states and modest differential expression results between aged and young cells are surprising in light of the dramatic differences in functional potential between aged and young cell populations (Chakkalakal et al., 2012; Cosgrove et al., 2014).”
From Aging induces aberrant state transition kinetics in murine muscle stem cells (2020) · cites this paper as Chakkalakal et al., 2012
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“…molecular and functional level, a host of aging phenotypes and associated mechanisms have been revealed in individual cell types (Shaw et al. 2010; Chakkalakal et al. 2012; Keyes et al. 2013; Liu et al. 2013; Flach et al. 2014; Blau et al. 2015; Brack andMuñoz-Cánoves 2016; Keyes and Fuchs 2018).”
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- Authors
- Chakkalakal, J. V., Jones, K. M., Basson, M. A., & Brack, A. S.
- Affiliations
- Massachusetts General Hospital (US)
- King's College London (GB)
- Harvard University (US)
- Corresponding author
- Brack, Andrew S.
- Venue
- Nature
- Published
- 2012-09-26
- Volume
- 490
- Issue
- 7420
- Pages
- 355-360
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3605795
- OpenAlex
- W2129976097
- Cited by
- 851
- References
- 59
- Citations by year
- 2026: 54 · 2025: 40 · 2024: 47 · 2023: 52 · 2022: 67 · 2021: 76 · 2020: 60 · 2019: 80 · 2018: 73 · 2017: 60 · 2016: 66 · 2015: 55 · 2014: 69 · 2013: 44 · 2012: 8
- FWCI
- 22.61
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- RePEc: Research Papers in Economics (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Research Portal (King's College London) (submittedVersion)
- Funders
- Wellcome Trust (WT091475, 091475)
- Biotechnology and Biological Sciences Research Council (BB/F017626/1)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR060868, R01AR061002)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Keywords
- muscle stem cells, satellite cells, stem cell quiescence, aging, stem cell niche, FGF2, SPRY1, FGF signaling, FGFR1, self-renewal, muscle regeneration, skeletal muscle fibers
- MeSH terms
- Aging, Animals, Cell Count, Cell Cycle, Cell Differentiation, Flow Cytometry, Homeostasis, Membrane Proteins, Mice, Inbred C57BL, Phosphoproteins, Time Factors, Signal Transduction, Fibroblast Growth Factor 2, Cellular Senescence, Muscle, Skeletal, Muscle Cells, Satellite Cells, Skeletal Muscle, Adaptor Proteins, Signal Transducing, Cyclin-Dependent Kinase Inhibitor p27, Mice, PAX7 Transcription Factor, Stem Cell Niche
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