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Cited by 443Muscle Physiology and DisordersMesenchymal stem cell researchNeurogenetic and Muscular Disorders Research

The central role of muscle stem cells in regenerative failure with aging

Open access
Blau, Helen M, Cosgrove, Benjamin D, Ho, Andrew T V·2015·Nature Medicine
DOI 10.1038/nm.3918PMC PMC4731230
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Abstract

Skeletal muscle mass, function, and repair capacity all progressively decline with aging, restricting mobility, voluntary function, and quality of life. Skeletal muscle repair is facilitated by a population of dedicated muscle stem cells (MuSCs), also known as satellite cells, that reside in anatomically defined niches within muscle tissues. In adult tissues, MuSCs are retained in a quiescent state until they are primed to regenerate damaged muscle through cycles of self-renewal divisions. With aging, muscle tissue homeostasis is progressively disrupted and the ability of MuSCs to repair injured muscle markedly declines. Until recently, this decline has been largely attributed to extrinsic age-related alterations in the microenvironment to which MuSCs are exposed. However, as highlighted in this Perspective, recent reports show that MuSCs also progressively undergo cell-intrinsic alterations that profoundly affect stem cell regenerative function with aging. A more comprehensive understanding of the interplay of stem cell-intrinsic and extrinsic factors will set the stage for improving cell therapies capable of restoring tissue homeostasis and enhancing muscle repair in the aged.

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Crossref · 10.1038/nm.3918

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Claims the paper makes

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  • Premisecitation

    Dedicated muscle stem cells, also called satellite cells, support repair of skeletal muscle.

    “Skeletal muscle repair is facilitated by a population of dedicated muscle stem cells (MuSCs), also known as satellite cells, that reside in anatomically defined niches within muscle tissues.”
    Quote in the paperSubstantial claim0 of 8 sources checked
    • cites [5] Bosnakovski, D. et al. Prospective isolation of skeletal muscle stem cells with a Pax7 reporter. Stem Cells 26, 3194–3204 (2008). source

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    • cites [6] Cerletti, M. et al. Highly efficient, functional engraftment of skeletal muscle stem cells in dystrophic muscles. Cell 134, 37–47 (2008). source

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    • cites [7] Kuang, S., Kuroda, K., Le Grand, F. & Rudnicki, M.A. Asymmetric self-renewal and commitment of satellite stem cells in muscle. Cell 129, 999–1010 (2007). source

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    • cites [8] Lepper, C. & Fan, C.M. Inducible lineage tracing of Pax7-descendant cells reveals embryonic origin of adult satellite cells. Genesis 48, 424–436 (2010). source

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    • cites [9] Montarras, D. et al. Direct isolation of satellite cells for skeletal muscle regeneration. Science 309, 2064–2067 (2005). source

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    • cites [10] Sacco, A., Doyonnas, R., Kraft, P., Vitorovic, S. & Blau, H.M. Self-renewal and expansion of single transplanted muscle stem cells. Nature 456, 502–506 (2008). source

      Not checked in the free run.

    • cites [11] von Maltzahn, J., Jones, A.E., Parks, R.J. & Rudnicki, M.A. Pax7 is critical for the normal function of satellite cells in adult skeletal muscle. Proc. Natl. Acad. Sci. USA 110, 16474–16479 (2013). source

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    • cites [12] Günther, S. et al. Myf5-positive satellite cells contribute to Pax7-dependent long-term maintenance of adult muscle stem cells. Cell Stem Cell 13, 590–601 (2013). source

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  • Premisecitation

    Recent work indicates that aging MuSCs acquire cell-intrinsic changes that strongly impair their regenerative function.

    “However, as highlighted in this Perspective, recent reports show that MuSCs also progressively undergo cell-intrinsic alterations that profoundly affect stem cell regenerative function with aging.”
    Quote in the paperSubstantial claim
  • Premisecitation

    In aging, the capacity of MuSCs to repair injured muscle declines markedly.

    “With aging, muscle tissue homeostasis is progressively disrupted and the ability of MuSCs to repair injured muscle markedly declines.”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [25] Price, F.D. et al. Inhibition of JAK-STAT signaling stimulates adult satellite cell function. Nat. Med. 20, 1174–1181 (2014). source

      Not checked in the free run.

    • cites [29] Cosgrove, B.D. et al. Rejuvenation of the muscle stem cell population restores strength to injured aged muscles. Nat. Med. 20, 255–264 (2014). source

      Not checked in the free run.

    • cites [55] Bernet, J.D. et al. p38 MAPK signaling underlies a cell-autonomous loss of stem cell self-renewal in skeletal muscle of aged mice. Nat. Med. 20, 265–271 (2014). source

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    • cites [56] Sousa-Victor, P. et al. Geriatric muscle stem cells switch reversible quiescence into senescence. Nature 506, 316–321 (2014). source

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  • Premisecitation

    During normal development, adult skeletal muscle growth is governed by homeostatic interactions among MuSCs, other resident cells, and the tissue microenvironment.

    “In the context of skeletal muscle tissue, homeostatic interactions between MuSCs, other resident cells, and the tissue microenvironment govern adult skeletal muscle growth during normal development.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [1] Buchman, T.G. The community of the self. Nature 420, 246–251 (2002). source

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  • Premisecitation

    In aged mice, MuSCs and their myogenic progeny encounter elevated circulating Wnt3a.

    “MuSCs and their myogenic progeny are exposed to increased levels of circulating Wnt3a (wingless-type MMTV integration site family, member 3A) in aged mice34.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [34] Brack, A.S. et al. Increased Wnt signaling during aging alters muscle stem cell fate and increases fibrosis. Science 317, 807–810 (2007). source

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  • May combine two claims. 62
  • Classified as probably not a substantial claim. 6

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    Interpretationcitation

    Together, these dysregulated signals impair MuSC-mediated myofiber repair and self-renewal in aged tissues and promote fibroblast generation.

    “Together, these dysregulated signals impair MuSC-mediated myofiber repair and stem cell self-renewal in aged tissues and lead to the generation of fibroblasts34.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [34] Brack, A.S. et al. Increased Wnt signaling during aging alters muscle stem cell fate and increases fibrosis. Science 317, 807–810 (2007). source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductcitation

    The original study did not assess the dimeric form.

    “This dimeric form was not assessed in the original study44.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [44] Loffredo, F.S. et al. Growth differentiation factor 11 is a circulating factor that reverses age-related cardiac hypertrophy. Cell 153, 828–839 (2013). source

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    Premisecitation

    Oxytocin promotes muscle regeneration in young adult mice, but its levels decline in aged mice.

    “In addition, in young adult mice, the hormone oxytocin promotes muscle regeneration, whereas in aged mice this hormone declines41.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [41] Elabd, C. et al. Oxytocin is an age-specific circulating hormone that is necessary for muscle maintenance and regeneration. Nat. Commun. 5, 4082 (2014). source

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  • May combine two claims.

    Premisecitation

    MuSCs are required for efficient repair of muscle damage, and ablating them in aged mice still impairs repair.

    “In adult muscles, MuSCs are essential for efficient repair of tissue damage. When MuSCs are conditionally ablated, even in aged mice, muscle repair is defective17.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [17] Fry, C.S. et al. Inducible depletion of satellite cells in adult, sedentary mice impairs muscle regenerative capacity without affecting sarcopenia. Nat. Med. 21, 76–80 (2015). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    When aged muscle is grafted into young rats, it gains mass and contractile strength, while young muscle grafted into aged hosts loses these properties.

    “Aged muscle tissues grafted into muscles of young rats exhibit increased muscle mass and contractile strength, and the converse is true for young grafts into aged hosts.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [32] Carlson, B.M. & Faulkner, J.A. Muscle transplantation between young and old rats: age of host determines recovery. Am. J. Physiol. 256, C1262–C1266 (1989). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In healthy muscle, feedback mechanisms ensure that asymmetric self-renewing divisions produce enough fusion-competent progenitors for myofiber repair and uncommitted quiescent stem cells that maintain the MuSC reservoir.

    “In healthy muscle tissues, feedback mechanisms ensure that asymmetric self-renewing divisions yield sufficient numbers of fusion-competent muscle progenitor cells that contribute to myofiber repair, and uncommitted stem cells that remain in the satellite cell position in a quiescent state and serve as a MuSC reservoir13–16.”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [13] Chakkalakal, J.V., Jones, K.M., Basson, M.A. & Brack, A.S. The aged niche disrupts muscle stem cell quiescence. Nature 490, 355–360 (2012). source

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    • cites [14] Sambasivan, R. et al. Pax7-expressing satellite cells are indispensable for adult skeletal muscle regeneration. Development 138, 3647–3656 (2011). source

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    • cites [15] Gopinath, S.D., Webb, A.E., Brunet, A. & Rando, T.A. FOXO3 promotes quiescence in adult muscle stem cells during the process of self-renewal. Stem Cell Rep. 2, 414–426 (2014). source

      Not checked in the free run.

    • cites [16] Rocheteau, P., Gayraud-Morel, B., Siegl-Cachedenier, I., Blasco, M.A. & Tajbakhsh, S. A subpopulation of adult skeletal muscle stem cells retains all template DNA strands after cell division. Cell 148, 112–125 (2012). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Adult MuSCs are generally marked by expression of the myogenic transcription factor Pax7.

    “Throughout adulthood, MuSCs, which are generally characterized by expression of the myogenic transcription factor Pax7 (ref. 2), are retained in a mitotically and metabolically quiescent state3,4.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [2] Seale, P., Asakura, A. & Rudnicki, M.A. The potential of muscle stem cells. Dev. Cell 1, 333–342 (2001). source

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  • May combine two claims.

    Interpretationreasoning

    The authors propose that aging combines a shift in extrinsic influences with heritable intrinsic changes in MuSCs to alter muscle tissue homeostasis, ultimately preventing regeneration needs from being met.

    “We propose that during aging, a shift in the balance of extrinsic influences in conjunction with accumulated heritable intrinsic changes within MuSCs alters muscle tissue homeostasis, so that ultimately the needs for regeneration cannot be met.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductcitation

    Parabiosis experiments are limited because the forced connection stresses the mice and the systemic changes occur amid chronic inflammation.

    “A caveat of these experiments is that young and aged mice in parabionts are stressed by their forced connection, and the observed systemic changes occur in the complex milieu of chronic inflammation36.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [36] Johansson, C.B. et al. Extensive fusion of haematopoietic cells with Purkinje neurons in response to chronic inflammation. Nat. Cell Biol. 10, 575–583 (2008). source

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    Premisecitation

    A second study confirmed the monomeric decrease but also measured dimeric forms and found that these increase cumulatively with aging.

    “The second study43 confirmed this observation, but also examined the active and more abundant dimeric forms and showed that they cumulatively increase with aging.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [43] Egerman, M.A. et al. GDF11 increases with age and inhibits skeletal muscle regeneration. Cell Metab. 22, 164–174 (2015). source

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    Premisecitation

    Wnt3a activates β-catenin signaling, promotes fibrogenic differentiation of muscle stem and progenitor cells, and opposes Notch signaling.

    “Wnt3a stimulates β-catenin signaling, which induces undesirable fibrogenic differentiation of muscle stem and progenitor cells34, and also antagonizes Notch signaling37.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [34] Brack, A.S. et al. Increased Wnt signaling during aging alters muscle stem cell fate and increases fibrosis. Science 317, 807–810 (2007). source

      Not checked in the free run.

    • cites [37] Brack, A.S., Conboy, I.M., Conboy, M.J., Shen, J. & Rando, T.A. A temporal switch from notch to Wnt signaling in muscle stem cells is necessary for normal adult myogenesis. Cell Stem Cell 2, 50–59 (2008). source

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  • May combine two claims.

    Premisecitation

    During adulthood, MuSCs remain mitotically and metabolically quiescent.

    “Throughout adulthood, MuSCs, which are generally characterized by expression of the myogenic transcription factor Pax7 (ref. 2), are retained in a mitotically and metabolically quiescent state3,4.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [3] Cheung, T.H. & Rando, T.A. Molecular regulation of stem cell quiescence. Nat. Rev. Mol. Cell Biol. 14, 329–340 (2013). source

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    • cites [4] Montarras, D., L'Honore, A. & Buckingham, M. Lying low but ready for action: the quiescent muscle satellite cell. FEBS J. 280, 4036–4050 (2013). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Follistatin and GASPs inhibit GDF11 and myostatin, and mice lacking one Fst allele or Gasp1/Gasp2 have smaller muscles with higher GDF11 and myostatin bioactivity.

    “Both follistatin and GASPs inhibit the activities of GDF11 and myostatin; accordingly, follistatin (Fst)-heterozygous47 and Gasp1-null or Gasp2-null48 mice have smaller muscles and increased GDF11 and myostatin bioactivity.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [47] Lee, S.J. et al. Regulation of muscle mass by follistatin and activins. Mol. Endocrinol. 24, 1998–2008 (2010). source

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    • cites [48] Lee, Y.S. & Lee, S.J. Regulation of GDF-11 and myostatin activity by GASP-1 and GASP-2. Proc. Natl. Acad. Sci. USA 110, E3713–E3722 (2013). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Aged MuSC populations show a higher fraction with reduced clonal proliferation, altered transcription factor profiles, elevated phosphorylated p38α/β MAPK, increased p16Ink4a, and elevated cytokines and cytokine receptors.

    “Aged MuSC populations are characterized by an increased proportion with reduced clonal proliferation capacity, altered profiles of transcription factor expression evident in single-cell RT-PCR and microarray assays, elevated phosphorylated p38α/β MAPK, increased expression of the senescence marker p16Ink4a, and elevated cytokines and cytokine receptors13,14,16.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [13] Chakkalakal, J.V., Jones, K.M., Basson, M.A. & Brack, A.S. The aged niche disrupts muscle stem cell quiescence. Nature 490, 355–360 (2012). source

      Not checked in the free run.

    • cites [14] Sambasivan, R. et al. Pax7-expressing satellite cells are indispensable for adult skeletal muscle regeneration. Development 138, 3647–3656 (2011). source

      Not checked in the free run.

    • cites [16] Rocheteau, P., Gayraud-Morel, B., Siegl-Cachedenier, I., Blasco, M.A. & Tajbakhsh, S. A subpopulation of adult skeletal muscle stem cells retains all template DNA strands after cell division. Cell 148, 112–125 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Aging does not change all MuSCs simultaneously; instead, the population becomes more heterogeneous and less regenerative because the dysfunctional subset progressively increases.

    “MuSCS do not simultaneously change with age. Instead, with aging, a shift toward a more heterogeneous, less regenerative MuSC population is observed. This results from a progressive increase in the subset of MuSCs that is dysfunctional in regeneration with age.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Single MuSCs can produce thousands of progeny, differentiate into myofibers, and self-renew after re-injury.

    “By using BLI, single MuSCs isolated from transgenic mice that ubiquitously express a luciferase transgene were shown to give rise to thousands of progeny, differentiate into myofibers, and self-renew upon re-injury10.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [10] Sacco, A., Doyonnas, R., Kraft, P., Vitorovic, S. & Blau, H.M. Self-renewal and expansion of single transplanted muscle stem cells. Nature 456, 502–506 (2008). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Together, these cell-autonomous changes restrict MuSC self-renewal and regenerative capacity.

    “Cumulatively, these cell autonomous alterations limit MuSC self-renewal and capacity for regeneration25,29,55,56.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [25] Price, F.D. et al. Inhibition of JAK-STAT signaling stimulates adult satellite cell function. Nat. Med. 20, 1174–1181 (2014). source

      Not checked in the free run.

    • cites [29] Cosgrove, B.D. et al. Rejuvenation of the muscle stem cell population restores strength to injured aged muscles. Nat. Med. 20, 255–264 (2014). source

      Not checked in the free run.

    • cites [55] Bernet, J.D. et al. p38 MAPK signaling underlies a cell-autonomous loss of stem cell self-renewal in skeletal muscle of aged mice. Nat. Med. 20, 265–271 (2014). source

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  • May combine two claims.

    Premisecitation

    MuSCs from older donors have marked deficits in self-renewal, expansion, and contribution to mature myofiber formation.

    “MuSCs from older donors exhibited marked deficits both in self-renewal and expansion and in their contributions to mature myofiber formation, the two hallmarks of stem cell function25,29,55,56.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [25] Price, F.D. et al. Inhibition of JAK-STAT signaling stimulates adult satellite cell function. Nat. Med. 20, 1174–1181 (2014). source

      Not checked in the free run.

    • cites [29] Cosgrove, B.D. et al. Rejuvenation of the muscle stem cell population restores strength to injured aged muscles. Nat. Med. 20, 255–264 (2014). source

      Not checked in the free run.

    • cites [55] Bernet, J.D. et al. p38 MAPK signaling underlies a cell-autonomous loss of stem cell self-renewal in skeletal muscle of aged mice. Nat. Med. 20, 265–271 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Rejuvenating aged MuSCs requires both biophysical and biochemical cues, suggesting that extrinsic and intrinsic factors must act synergistically.

    “Thus, a combination of biophysical and biochemical cues is required to rejuvenate the aged MuSC population, suggesting that a synergistic interplay of extrinsic and intrinsic factors is necessary.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [29] Cosgrove, B.D. et al. Rejuvenation of the muscle stem cell population restores strength to injured aged muscles. Nat. Med. 20, 255–264 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Ablating p16Ink4a-expressing MuSCs and other senescent cells reduces muscle wasting and improves treadmill performance.

    “Conditional ablation of this p16Ink4a-expressing MuSC population and other senescent cells ameliorates muscle wasting, leading to improved performance in treadmill exercise tests60.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [60] Baker, D.J. et al. Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature 479, 232–236 (2011). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    These transplantation results contrast with parabiosis and suggest that aged or rejuvenated MuSC states involve a cell-autonomous memory independent of extrinsic regulators.

    “These results are in contrast with those obtained by parabiosis and suggest that irrespective of extrinsic regulators there is a cell-autonomous ‘memory’ for the aged or rejuvenated MuSC state.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The changes include cell-autonomous activation of p38α/β MAPK, FGFR-Sprouty1, Jak2-Stat3, and p16Ink4a-Rb pathways.

    “These changes include aberrant and cell-autonomous activation of the stress-associated p38α/β mitogen-activated protein kinase (MAPK) signaling axis, the growth factor-stimulated FGFR–Sprouty1 signaling axis, the cytokine-stimulated Jak2–Stat3 signaling axis, and p16Ink4a (also known as Cdkn2a)–Rb cell cycle inhibitors25,27,29,55,56 (Fig. 2).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [25] Price, F.D. et al. Inhibition of JAK-STAT signaling stimulates adult satellite cell function. Nat. Med. 20, 1174–1181 (2014). source

      Not checked in the free run.

    • cites [27] Tierney, M.T. et al. STAT3 signaling controls satellite cell expansion and skeletal muscle repair. Nat. Med. 20, 1182–1186 (2014). source

      Not checked in the free run.

    • cites [29] Cosgrove, B.D. et al. Rejuvenation of the muscle stem cell population restores strength to injured aged muscles. Nat. Med. 20, 255–264 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Transplanted FACS-isolated MuSCs localize to the classic satellite cell niche, identifying them as the satellite cells first described by electron microscopy in 1961.

    “Indeed, a study using the Pax3-GFP reporter mice revealed that transplanted FACS-isolated MuSCs home to the classic ‘satellite cell niche’9, and hence constitute the satellite cells first identified by electron microscopy in 1961 (ref. 22).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [9] Montarras, D. et al. Direct isolation of satellite cells for skeletal muscle regeneration. Science 309, 2064–2067 (2005). source

      Not checked in the free run.

    • cites [22] Mauro, A. Satellite cell of skeletal muscle fibers. J. Biophys. Biochem. Cytol. 9, 493–495 (1961). source

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  • May combine two claims.

    Premisecitation

    In mice, lentiviral knockdown of p16Ink4a or transient ex vivo inhibition of p38α/β MAPK stops progression to senescence and rejuvenates aged MuSCs.

    “Notably lentivirally-mediated genetic knockdown of p16Ink4a (officially known as Cdkn2a) (ref. 56) or transient biochemical inhibition of p38α/β MAPK29 ex vivo halts progression toward senescence and facilitates rejuvenation of the aged MuSC population in mouse.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [56] Sousa-Victor, P. et al. Geriatric muscle stem cells switch reversible quiescence into senescence. Nature 506, 316–321 (2014). source

      Not checked in the free run.

    • cites [29] Cosgrove, B.D. et al. Rejuvenation of the muscle stem cell population restores strength to injured aged muscles. Nat. Med. 20, 255–264 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    These findings suggest that changing MuSC function or phenotype in aged muscle will improve repair and may also alleviate sarcopenia.

    “These findings suggest that altering the function or phenotype of MuSCs in aged muscle tissue will enhance muscle repair29 and may also ameliorate sarcopenia61.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [29] Cosgrove, B.D. et al. Rejuvenation of the muscle stem cell population restores strength to injured aged muscles. Nat. Med. 20, 255–264 (2014). source

      Not checked in the free run.

    • cites [61] Hall, J.K., Banks, G.B., Chamberlain, J.S. & Olwin, B.B. Prevention of muscle aging by myofiber-associated satellite cell transplantation. Sci. Transl. Med. 2, 57ra83 (2010). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    p38α/β MAPK becomes progressively disrupted in aged MuSCs and lies downstream of TNF-α and IL-1.

    “Indeed, one of the signaling pathways that is progressively disrupted in aged MuSCs is p38α/β MAPK, which is known to be downstream of TNF-α and IL-1 (refs. 27,56,57).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [27] Tierney, M.T. et al. STAT3 signaling controls satellite cell expansion and skeletal muscle repair. Nat. Med. 20, 1182–1186 (2014). source

      Not checked in the free run.

    • cites [56] Sousa-Victor, P. et al. Geriatric muscle stem cells switch reversible quiescence into senescence. Nature 506, 316–321 (2014). source

      Not checked in the free run.

    • cites [57] Palacios, D. et al. TNF/p38alpha/polycomb signaling to Pax7 locus in satellite cells links inflammation to the epigenetic control of muscle regeneration. Cell Stem Cell 7, 455–469 (2010). source

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  • May combine two claims.

    Premisecitation

    Injured young adult muscle mounts a temporally regulated, acute, transient immune response that is critical for regeneration, unlike aged muscle.

    “Upon injury to young adult muscle, in contrast to injury to aged muscles65, there is a temporally regulated acute and transient immune response that is critical to muscle regeneration66 (Fig. 2).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [65] Bouché, M., Munoz-Canoves, P., Rossi, F. & Coletti, D. Inflammation in muscle repair, aging, and myopathies. Biomed Res. Int. 2014, 821950 (2014). source

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    • cites [66] Tidball, J.G. Mechanisms of muscle injury, repair, and regeneration. Compr. Physiol. 1, 2029–2062 (2011). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    These findings suggest that rejuvenation expands a residual highly regenerative subset rather than converting dysfunctional cells into functional ones.

    “These findings suggest that rejuvenation of the aged MuSC population results from an expansion of a subset of residual highly regenerative cells rather than a conversion of dysfunctional cells to a functional cell state.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [29] Cosgrove, B.D. et al. Rejuvenation of the muscle stem cell population restores strength to injured aged muscles. Nat. Med. 20, 255–264 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    With aging, MuSCs shift from quiescence to overactivation marked by persistent p38α/β MAPK activity, eventually causing premature differentiation, senescence, and stem cell exhaustion.

    “As a result, in the course of aging, MuSCs shift from a quiescent phenotype to an over-activated phenotype characterized by persistent p38α/β MAPK activity that eventually leads to premature differentiation senescence and stem cell exhaustion25,29,55,56.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [25] Price, F.D. et al. Inhibition of JAK-STAT signaling stimulates adult satellite cell function. Nat. Med. 20, 1174–1181 (2014). source

      Not checked in the free run.

    • cites [29] Cosgrove, B.D. et al. Rejuvenation of the muscle stem cell population restores strength to injured aged muscles. Nat. Med. 20, 255–264 (2014). source

      Not checked in the free run.

    • cites [55] Bernet, J.D. et al. p38 MAPK signaling underlies a cell-autonomous loss of stem cell self-renewal in skeletal muscle of aged mice. Nat. Med. 20, 265–271 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In chronic damage such as mdx mouse muscle, FAPs persist and differentiate into fibro-adipocytes, presumably because TGF-β1 increases.

    “Notably, when damage is chronic, as in muscles of mdx mice, the FAP population persists and differentiates into fibro-adipocytes presumably due to an increase in TGF-β1 (ref. 79).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [79] Lemos, D.R. et al. Nilotinib reduces muscle fibrosis in chronic muscle injury by promoting TNF-mediated apoptosis of fibro/adipogenic progenitors. Nat. Med. 21, 786–794 (2015). source

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  • May combine two claims.

    Premisecitation

    Ablating muscle connective tissue fibroblasts using TCF4-mediated diphtheria toxin promotes MuSC differentiation, depletes stem cell niches, and impairs regeneration.

    “Genetic ablation of fibroblasts in muscle connective tissue via TCF4-mediated diphtheria toxin expression promotes MuSC differentiation, leading to depletion of stem cell niches, which impairs muscle regeneration80.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [80] Murphy, M.M., Lawson, J.A., Mathew, S.J., Hutcheson, D.A. & Kardon, G. Satellite cells, connective tissue fibroblasts and their interactions are crucial for muscle regeneration. Development 138, 3625–3637 (2011). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Macrophages drive a pro-inflammatory phase secreting IL-6, TNF-α, and IFN-γ that promotes myogenic proliferation, then an anti-inflammatory phase secreting TGF-β, IGF-1, and IL-10 that supports myogenic differentiation.

    “The macrophages induce a pro-inflammatory phase that in muscle entails secretion of cytokines such as IL-6, TNF-α and IFN-γ, which promote myogenic cell proliferation. This phase is followed by an anti-inflammatory phase during which macrophages secrete TGF-β, IGF-1 and IL-10, which facilitate myogenic differentiation55,67,68.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [55] Bernet, J.D. et al. p38 MAPK signaling underlies a cell-autonomous loss of stem cell self-renewal in skeletal muscle of aged mice. Nat. Med. 20, 265–271 (2014). source

      Not checked in the free run.

    • cites [67] Bosurgi, L., Manfredi, A.A. & Rovere-Querini, P. Macrophages in injured skeletal muscle: a perpetuum mobile causing and limiting fibrosis, prompting or restricting resolution and regeneration. Front. Immunol. 2, 62 (2011). source

      Not checked in the free run.

    • cites [68] Chazaud, B. Macrophages: supportive cells for tissue repair and regeneration. Immunobiology 219, 172–178 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In geriatric mice, chronic p16Ink4a expression causes senescent MuSC accumulation and impaired regeneration, which conditional ablation of senescent cells can circumvent.

    “For example, chronic p16Ink4a expression in geriatric mice leads to an accumulation of senescent MuSCs and impaired regeneration, which can be circumvented by conditional ablation of the senescent cells56.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [56] Sousa-Victor, P. et al. Geriatric muscle stem cells switch reversible quiescence into senescence. Nature 506, 316–321 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    These results suggest that transient SASP component expression, including inflammatory cytokines, can enhance muscle regeneration, while persistent expression impairs repair.

    “These results suggest that in muscle, the transient expression of SASP components, such as inflammatory cytokines, can augment regeneration, whereas persistent expression of SASP components impedes repair (Fig. 2).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [56] Sousa-Victor, P. et al. Geriatric muscle stem cells switch reversible quiescence into senescence. Nature 506, 316–321 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Rejuvenation strategies appear to overcome the predominance of dysfunctional MuSCs by expanding a still-youthful subset, shifting the aged population toward enhanced function that can restore muscle homeostasis and improve regeneration.

    “Thus, rejuvenation strategies appear to overcome the prevalence of dysfunctional MuSCs within the aging population by augmenting a still-youthful subset. As a result, there is a shift in the aged MuSC population toward MuSCs with enhanced function, capable of restoring muscle homeostasis, and improving regeneration.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Sprouty1 negatively regulates receptor tyrosine kinase signaling and attenuates FGF2-FGFR signaling, so MuSCs with high Sprouty1 remain quiescent.

    “Notably, recent reports demonstrate that Sprouty1, a negative regulator of receptor tyrosine kinase signaling, attenuates FGF2–FGFR signaling13. As a result, MuSCs with elevated Sprouty1 levels remain quiescent.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [13] Chakkalakal, J.V., Jones, K.M., Basson, M.A. & Brack, A.S. The aged niche disrupts muscle stem cell quiescence. Nature 490, 355–360 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A transient inflammatory response aids regeneration, but persistent inflammation typical of chronic muscle disease hinders it.

    “Thus, although a transient inflammatory response is beneficial to regeneration, the persistent inflammation that is characteristic of chronic muscle disease impedes regeneration65.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [65] Bouché, M., Munoz-Canoves, P., Rossi, F. & Coletti, D. Inflammation in muscle repair, aging, and myopathies. Biomed Res. Int. 2014, 821950 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Together, findings show that aging MuSCs progressively accumulate intrinsic changes that impair regenerative function, persist after transplantation into young or aged microenvironments, and are inherited by progeny.

    “Together, these findings show that intrinsic changes progressively accumulate in MuSCs during aging, which affect their regenerative function25,29,55,56. Moreover, these changes are not altered by transplantation into a youthful or aged microenvironment and are heritably transmitted from the stem cells to their progeny29,56.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [25] Price, F.D. et al. Inhibition of JAK-STAT signaling stimulates adult satellite cell function. Nat. Med. 20, 1174–1181 (2014). source

      Not checked in the free run.

    • cites [29] Cosgrove, B.D. et al. Rejuvenation of the muscle stem cell population restores strength to injured aged muscles. Nat. Med. 20, 255–264 (2014). source

      Not checked in the free run.

    • cites [55] Bernet, J.D. et al. p38 MAPK signaling underlies a cell-autonomous loss of stem cell self-renewal in skeletal muscle of aged mice. Nat. Med. 20, 265–271 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In geriatric mice, injury elevates IL-6 signaling, which leads to MuSC exhaustion and muscle atrophy.

    “Indeed, in geriatric mice (24–28 months), IL-6 signaling has been shown to be elevated after injury, leading to muscle stem cell exhaustion and consequent muscle atrophy56.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [56] Sousa-Victor, P. et al. Geriatric muscle stem cells switch reversible quiescence into senescence. Nature 506, 316–321 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Properly regulated fibroblasts support regeneration, whereas excess fibroblasts, as in aged tissues, harm it.

    “Thus, when fibroblasts are appropriately regulated, they are beneficial to regeneration, but when in excess, as seen in aged tissues, they are detrimental.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    MSCs, including FAPs, affect MuSC function; MSCs secrete Wnt ligands and FAPs secrete IL-6.

    “Mesenchymal stem cells (MSCs), which include the fibro-adipogenic progenitors (FAPs)75,76 have also been shown to impact MuSC function. MSCs secrete a number of Wnt ligands, and FAPs are known to secrete IL-6 (refs. 75,77).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [75] Joe, A.W. et al. Muscle injury activates resident fibro/adipogenic progenitors that facilitate myogenesis. Nat. Cell Biol. 12, 153–163 (2010). source

      Not checked in the free run.

    • cites [76] Uezumi, A., Fukada, S., Yamamoto, N., Takeda, S. & Tsuchida, K. Mesenchymal progenitors distinct from satellite cells contribute to ectopic fat cell formation in skeletal muscle. Nat. Cell Biol. 12, 143–152 (2010). source

      Not checked in the free run.

    • cites [77] Pretheeban, T., Lemos, D.R., Paylor, B., Zhang, R.H. & Rossi, F.M. Role of stem/progenitor cells in reparative disorders. Fibrogenesis Tissue Repair 5, 20 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Aged muscle accumulates senescent cells that remain alive but stop dividing and secrete a suite of cytokines, growth factors, and proteases known as SASP.

    “In aged muscle, senescent cells accumulate that are alive, but cease to divide. Senescent cells produce a suite of cytokines, growth factors, and proteases, known as the senescence-associated secretory phenotype (SASP)73.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [73] Coppé, J.P. et al. Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biol. 6, 2853–2868 (2008). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In aging, MuSC Sprouty1 expression falls sharply, reducing quiescence and increasing activation, and this is worsened by aged muscle fibers secreting more FGF-2.

    “However, during aging, Sprouty1 expression dramatically declines in MuSCs, leading to a reduction in quiescent cells and increased activation. This effect is further exacerbated by an increase in FGF-2 secretion by the muscle fiber itself in aged muscle tissues.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [13] Chakkalakal, J.V., Jones, K.M., Basson, M.A. & Brack, A.S. The aged niche disrupts muscle stem cell quiescence. Nature 490, 355–360 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Aged MuSCs secrete IL-18 and geriatric MuSCs secrete IL-6, which act autocrinely to stimulate MuSC proliferation.

    “Aged and geriatric MuSCs secrete IL-18 and IL-6, respectively, which act in an autocrine manner to induce proliferation of the MuSC population25,56.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [25] Price, F.D. et al. Inhibition of JAK-STAT signaling stimulates adult satellite cell function. Nat. Med. 20, 1174–1181 (2014). source

      Not checked in the free run.

    • cites [56] Sousa-Victor, P. et al. Geriatric muscle stem cells switch reversible quiescence into senescence. Nature 506, 316–321 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    These findings highlight interplay between extrinsic and intrinsic regulators of MuSC function and that homeostasis between them is crucial.

    “These findings highlight the interplay between extrinsic and intrinsic regulators of MuSC function and that homeostasis between the two is crucial.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationcitation

    Such alterations could cause YAP/TAZ translocation to MuSC nucleus, changing differentiation-associated gene expression, as shown in other cell types.

    “Such alterations could result in translocation of the YAP/TAZ complex from the cytoplasm to the nucleus of MuSCs, leading to changes in differentiation-associated gene expression, as shown in various cell types including mammary epithelial and mesenchymal stem cells103,104.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [103] Dupont, S. et al. Role of YAP/TAZ in mechanotransduction. Nature 474, 179–183 (2011). source

      Not checked in the free run.

    • cites [104] Pelissier, F.A. et al. Age-related dysfunction in mechanotransduction impairs differentiation of human mammary epithelial progenitors. Cell Rep 7, 1926–1939 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Rigidity alone does not maintain aged stem cell function in culture; a combination of 12-kPa rigidity and p38α/β MAPK inhibitor is necessary.

    “Notably, rigidity per se does not maintain aged stem cell function in culture. Instead, a combination of biophysical (12-kPa rigidity) and biochemical cues (p38α/β MAPK inhibitor) is necessary29.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [29] Cosgrove, B.D. et al. Rejuvenation of the muscle stem cell population restores strength to injured aged muscles. Nat. Med. 20, 255–264 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    ECM changes likely contribute to disruption of muscle tissue homeostasis and regenerative failure in aging, though effects on MuSC function in aging remain to be determined.

    “Although the effects of ECM changes on MuSC function in the course of aging remain to be determined, they are likely to contribute to the disruption of muscle tissue homeostasis and regenerative failure.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Aging alters composition and mechanics of MuSC niche, and these alterations can impede MuSC self-renewal after injury.

    “These results demonstrate that the composition and mechanics of the MuSC niche are altered with aging, and that these alterations can impede MuSC self-renewal in response to injury.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The myofiber ECM shifts from laminin-rich to collagen IV-enriched and collagen VI-reduced with aging.

    “The normally laminin-rich myofiber ECM shifts toward a composition enhanced in collagen IV (refs. 88,89), but with reduced collagen VI levels90.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [88] Kovanen, V., Suominen, H., Risteli, J. & Risteli, L. Type IV collagen and laminin in slow and fast skeletal muscle in rats–effects of age and life-time endurance training. Coll. Relat. Res. 8, 145–153 (1988). source

      Not checked in the free run.

    • cites [89] Alexakis, C., Partridge, T. & Bou-Gharios, G. Implication of the satellite cell in dystrophic muscle fibrosis: a self-perpetuating mechanism of collagen overproduction. Am. J. Physiol. Cell Physiol. 293, C661–C669 (2007). source

      Not checked in the free run.

    • cites [90] Scimè, A. et al. Transcriptional profiling of skeletal muscle reveals factors that are necessary to maintain satellite cell integrity during ageing. Mech. Ageing Dev. 131, 9–20 (2010). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Fibronectin binding to Syndecan4/Frizzled disrupts asymmetric MuSC self-renewal, promoting Wnt7a-mediated symmetric expansion.

    “Fibronectin binding to the Syndecan4/Frizzled complex disrupts the asymmetric self-renewal of MuSCs, thereby promoting Wnt7a-mediated symmetrical muscle stem cell expansion100.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [100] Bentzinger, C.F. et al. Fibronectin regulates Wnt7a signaling and satellite cell expansion. Cell Stem Cell 12, 75–87 (2013). source

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    With aging, persistent inflammation disrupts the MMP-TIMP balance, increasing fibrosis, altering muscle ECM composition, and raising tissue rigidity.

    “In aging, this balance is disrupted by a persistent inflammatory response that increases fibrosis, leading to altered composition of the muscle tissue ECM and increased tissue rigidity.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    MuSC self-renewal function depends heavily on rigidity; on traditional plastic dishes, stem cell function is lost.

    “The maintenance of MuSC self-renewal function relies heavily on rigidity, as when plated on traditional plastic dishes, stem cell function is lost.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [31] Gilbert, P.M. et al. Substrate elasticity regulates skeletal muscle stem cell self-renewal in culture. Science 329, 1078–1081 (2010). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    During aging, fibrotic and adipogenic cells increase in muscle and myofiber ECM composition is altered, affecting MuSC microenvironment.

    “During aging, fibrotic and adipogenic cells increase in muscle and the extracellular matrix composition of myofibers is altered, affecting the biochemical and biophysical microenvironment of muscle stem cells87.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [87] Snow, M.H. The effects of aging on satellite cells in skeletal muscles of mice and rats. Cell Tissue Res. 185, 399–408 (1977). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    p38α/β MAPK in complex with polycomb repressive complex 2 leads to H3K27me mark on Pax7 promoter and could repress this gene.

    “Additionally, p38α/β MAPK, which is known to be in a complex with polycomb repressive complex 2, leads to the H3K27me repressive mark on the Pax7 promoter, could have a role in this gene repression57.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [57] Palacios, D. et al. TNF/p38alpha/polycomb signaling to Pax7 locus in satellite cells links inflammation to the epigenetic control of muscle regeneration. Cell Stem Cell 7, 455–469 (2010). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Much softer or more rigid substrates cause loss of MuSCs via decreased survival or increased myogenic commitment.

    “In contrast, much softer or more rigid substrates result in a loss of MuSCs owing to decreased survival or increased myogenic commitment31.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [31] Gilbert, P.M. et al. Substrate elasticity regulates skeletal muscle stem cell self-renewal in culture. Science 329, 1078–1081 (2010). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Substrates with stiffness of young adult skeletal muscle (~12 kPa) promote MuSC self-renewal and myoblast differentiation.

    “In studies using biomimetic niches, substrates with an elastic stiffness of young adult skeletal muscle (∼12 kPa Young's modulus, the characteristic elastic rigidity of a material), which is five orders of magnitude softer than traditonal tissue culture plastic), promote MuSC self-renewal29,31 and myoblast differentiation94,95 (Fig. 4).”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [29] Cosgrove, B.D. et al. Rejuvenation of the muscle stem cell population restores strength to injured aged muscles. Nat. Med. 20, 255–264 (2014). source

      Not checked in the free run.

    • cites [31] Gilbert, P.M. et al. Substrate elasticity regulates skeletal muscle stem cell self-renewal in culture. Science 329, 1078–1081 (2010). source

      Not checked in the free run.

    • cites [94] Engler, A.J. et al. Myotubes differentiate optimally on substrates with tissue-like stiffness: pathological implications for soft or stiff microenvironments. J. Cell Biol. 166, 877–887 (2004). source

      Not checked in the free run.

    • cites [95] Boonen, K.J., Rosaria-Chak, K.Y., Baaijens, F.P., van der Schaft, D.W. & Post, M.J. Essential environmental cues from the satellite cell niche: optimizing proliferation and differentiation. Am. J. Physiol. Cell Physiol. 296, C1338–C1345 (2009). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    ECM and signaling proteins like fibronectin or Wnt7a direct symmetric MuSC self-renewal divisions; their decline in aging niches could exhaust the stem cell pool.

    “The ECM and signaling proteins in the microenvironment, such as fibronectin or Wnt7a, direct symmetric MuSC self-renewal divisions, and a decline in their abundance in muscle stem cell niches in aging could result in exhaustion of the stem cell pool100,”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [100] Bentzinger, C.F. et al. Fibronectin regulates Wnt7a signaling and satellite cell expansion. Cell Stem Cell 12, 75–87 (2013). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In other cell systems, matrix elasticity is sensed by integrin-focal adhesion complexes and actin-myosin network, altering RhoA GTPase activity.

    “Although these mechanisms have not been fully elucidated with respect to MuSC mechanosensitivity, in other cell systems, matrix elasticity is sensed by integrin-focal adhesion complexes and their engagement with the actin-myosin network, causing alterations in RhoA GTPase activity102.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [102] Halder, G., Dupont, S. & Piccolo, S. Transduction of mechanical and cytoskeletal cues by YAP and TAZ. Nat. Rev. Mol. Cell Biol. 13, 591–600 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Extrinsic serum factors can rejuvenate regenerative function, but intrinsic changes in MuSCs accumulating with aging can also profoundly impact regeneration.

    “Remarkably, although as shown by parabiosis, extrinsic serum factors can rejuvenate regenerative function, intrinsic changes within MuSCs that accumulate with aging can also profoundly impact regeneration (Figs. 2 and 3).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Syndecan3 facilitates Notch activation, promoting MuSC self-renewal and inhibiting differentiation.

    “Syndecan3, a transmembrane heparan sulfate proteoglycan (HSPG) facilitates Notch activation, which promotes MuSC self renewal and inhibits differentiation98.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [98] Pisconti, A., Cornelison, D.D., Olguin, H.C., Antwine, T.L. & Olwin, B.B. Syndecan-3 and Notch cooperate in regulating adult myogenesis. J. Cell Biol. 190, 427–441 (2010). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Aging-related perturbations in FGFR-p38 signaling disrupt asymmetric division, increasing symmetrically committed cells.

    “Perturbations in the FGFR–p38 signaling axis that arise in aging disrupt this asymmetric division mechanism, leading to an increase in symmetrically committed cells55.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [55] Bernet, J.D. et al. p38 MAPK signaling underlies a cell-autonomous loss of stem cell self-renewal in skeletal muscle of aged mice. Nat. Med. 20, 265–271 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Collagen VI increases satellite cell numbers and promotes regeneration.

    “Collagen VI increases satellite cell numbers and promotes regeneration99.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [99] Urciuolo, A. et al. Collagen VI regulates satellite cell self-renewal and muscle regeneration. Nat. Commun. 4, 1964 (2013). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    MuSCs are heterogeneous even in young mice, and heterogeneity increases with aging.

    “MuSCs are not a homogeneous population even in young mice, and MuSC heterogeneity increases during aging14,16,25,29,56,62–64.”
    Quote in the paperSubstantial claim0 of 8 sources checked
    • cites [14] Sambasivan, R. et al. Pax7-expressing satellite cells are indispensable for adult skeletal muscle regeneration. Development 138, 3647–3656 (2011). source

      Not checked in the free run.

    • cites [16] Rocheteau, P., Gayraud-Morel, B., Siegl-Cachedenier, I., Blasco, M.A. & Tajbakhsh, S. A subpopulation of adult skeletal muscle stem cells retains all template DNA strands after cell division. Cell 148, 112–125 (2012). source

      Not checked in the free run.

    • cites [25] Price, F.D. et al. Inhibition of JAK-STAT signaling stimulates adult satellite cell function. Nat. Med. 20, 1174–1181 (2014). source

      Not checked in the free run.

    • cites [29] Cosgrove, B.D. et al. Rejuvenation of the muscle stem cell population restores strength to injured aged muscles. Nat. Med. 20, 255–264 (2014). source

      Not checked in the free run.

    • cites [56] Sousa-Victor, P. et al. Geriatric muscle stem cells switch reversible quiescence into senescence. Nature 506, 316–321 (2014). source

      Not checked in the free run.

    • cites [62] Chakkalakal, J.V. et al. Early forming label-retaining muscle stem cells require p27kip1 for maintenance of the primitive state. Development 141, 1649–1659 (2014). source

      Not checked in the free run.

    • cites [63] Conboy, M.J., Karasov, A.O. & Rando, T.A. High incidence of non-random template strand segregation and asymmetric fate determination in dividing stem cells and their progeny. PLoS Biol. 5, e102 (2007). source

      Not checked in the free run.

    • cites [64] Shinin, V., Gayraud-Morel, B., Gomes, D. & Tajbakhsh, S. Asymmetric division and cosegregation of template DNA strands in adult muscle satellite cells. Nat. Cell Biol. 8, 677–687 (2006). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S1 (asserted), S3 (load-bearing).

    Interpretationcitation

    A short-term stem cell memory may be reinforced and committed to long-term memory by feedback signaling between impaired senescent MuSCs and youthful MuSCs, similar to the 'bad neighbors, good citizens' model.

    “We hypothesize that, in part, a short-term stem cell memory may be re-enforced and committed to long-term memory by feedback signaling between more ‘impaired senescent’ MuSCs and ‘youthful’ MuSCs, similar to that of the ‘bad neighbors, good citizens’ model described during cellular senescence112.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [112] Campisi, J. Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors. Cell 120, 513–522 (2005). source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    Aberrantly regulated signaling and transcription factors likely cause epigenetic changes in aged MuSCs that account for heritable memory in serial transplants.

    “Aberrantly regulated signaling and transcription factors are likely to lead to epigenetic changes in aged MuSCs that account for their heritable memory in serial transplants;”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Aged or geriatric MuSCs serially transplanted into young recipients have potent regenerative capacity, whereas rejuvenated MuSCs transplanted into aged or geriatric mice are impaired.

    “aged or geriatric MuSCs serially transplanted into young recipients have potent regenerative capacity, whereas rejuvenated MuSCs transplanted into aged or geriatric mice are impaired25,27,29,55,56.”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [25] Price, F.D. et al. Inhibition of JAK-STAT signaling stimulates adult satellite cell function. Nat. Med. 20, 1174–1181 (2014). source

      Not checked in the free run.

    • cites [27] Tierney, M.T. et al. STAT3 signaling controls satellite cell expansion and skeletal muscle repair. Nat. Med. 20, 1182–1186 (2014). source

      Not checked in the free run.

    • cites [29] Cosgrove, B.D. et al. Rejuvenation of the muscle stem cell population restores strength to injured aged muscles. Nat. Med. 20, 255–264 (2014). source

      Not checked in the free run.

    • cites [55] Bernet, J.D. et al. p38 MAPK signaling underlies a cell-autonomous loss of stem cell self-renewal in skeletal muscle of aged mice. Nat. Med. 20, 265–271 (2014). source

      Not checked in the free run.

    • cites [56] Sousa-Victor, P. et al. Geriatric muscle stem cells switch reversible quiescence into senescence. Nature 506, 316–321 (2014). source

      Not checked in the free run.

67 of 67

  • The paper relies on this without support.

    Intrinsic changes in aged MuSCs include constitutively phosphorylated p38α/β MAPK, Rb, Stat3, and p16Ink4a.

    “These intrinsic changes include constitutively phosphorylated p38α/β MAPK, Rb, Stat3, and p16Ink4a.”
1 of 1

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Tissue damage upon aging affects the extracellular matrix, which further alters stem cell niches regulating stem cell-regenerative functions.

    “Tissue damage upon aging affects the extracellular matrix, which further alters stem cell niches regulating stem cell-regenerative functions (Blau et al., 2015)”

    From Canonical Wnt Signaling Ameliorates Aging of Intestinal Stem Cells (2017) · cites this paper as Blau et al., 2015

  • As murine-muscle stem cells (MuSCs) age, the proportion of cells in regenerative states declines, and the overall regenerative capacity of the stem cell pool is greatly diminished.

    “As murine-muscle stem cells (MuSCs) age, the proportion of cells in regenerative states declines, and the overall regenerative capacity of the stem cell pool is greatly diminished (Blau et al., 2015; Brack and Muñoz-Cánoves, 2016).”

    From Aging induces aberrant state transition kinetics in murine muscle stem cells (2020) · cites this paper as Blau et al., 2015

  • 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 Blau et al., 2015

  • In vitro MuSC activation recapitulates many aspects of in vivo activation.

    “However, our in vitro assay allows for a homogeneous activation stimulus across all cells, unlike in vivo injury models and previous work demonstrating that in vitro MuSC activation recapitulates many aspects of in vivo activation (Blau et al., 2015; Cornelison and Wold, 1997; Cosgrove et al., 2014; Gilbert et al., 2010).”

    From Aging induces aberrant state transition kinetics in murine muscle stem cells (2020) · cites this paper as Blau et al., 2015

  • The regenerative capacity of SCs is influenced by both intrinsic modulators and the extrinsic microenvironment.

    “The regenerative capacity of SCs is influenced by both intrinsic modulators and the extrinsic microenvironment13–15.”

    From In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche (2021) · cites this paper as [13]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Opposite outcomes reported for aged stem cells transplanted into young recipients

    Minor

    The conclusion says aged or geriatric MuSCs retain potent regenerative capacity after serial transplantation into young recipients. Earlier, the paper says stem cells from aged-MuSC transplants remain severely defective when transplanted into secondary young recipients.

1 of 1

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Authors
Blau, H. M., Cosgrove, B. D., & Ho, A. T. V.
Affiliations
  • Stanford Medicine (US)
  • Cornell University (US)
Corresponding author
Blau, Helen M
ORCID
Venue
Nature Medicine
Publisher
Springer Science and Business Media LLC
Published
2015-08
Volume
21
Issue
8
Pages
854-862
ISSN
  • 1078-8956 (ISSN-L)
  • 1546-170X
DOI
10.1038/nm.3918
PMC
PMC4731230
OpenAlex
W2230902569
Cited by
437
References
117
Citations by year
2026: 37 · 2025: 33 · 2024: 41 · 2023: 36 · 2022: 41 · 2021: 45 · 2020: 48 · 2019: 36 · 2018: 49 · 2017: 34 · 2016: 35 · 2015: 2
FWCI
3.88
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Medical University of South Carolina
  • National Institute on Aging (AG-020961, R00AG042491, AG044815, R01AG009521, R21AG044815, R01AG020961)
  • National Heart, Lung, and Blood Institute (U01HL100397)
  • National Institute of Neurological Disorders and Stroke (R01NS089533, NS089533)
  • National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR063963, AR063963)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
  • Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
  • Health Sciences › Medicine › Genetics › Neurogenetic and Muscular Disorders Research
Keywords
muscle stem cells, satellite cells, skeletal muscle aging, muscle regeneration, stem cell quiescence, self-renewal, extrinsic aging, muscle microenvironment, cell therapy, tissue homeostasis
MeSH terms
Aging, Animals, Homeostasis, Humans, Inflammation, Regeneration, Stem Cells, Cell Polarity, Cellular Senescence, Muscle, Skeletal, Bone Morphogenetic Proteins, p38 Mitogen-Activated Protein Kinases, Growth Differentiation Factors

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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-06.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.

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