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

In the paper

“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.”

What the sources say

• Not checked yetcites [5] Bosnakovski, D. et al. Prospective isolation of skeletal muscle stem cells with a Pax7 reporter. Stem Cells 26, 3194–3204 (2008). source
• Not checked yetcites [6] Cerletti, M. et al. Highly efficient, functional engraftment of skeletal muscle stem cells in dystrophic muscles. Cell 134, 37–47 (2008). source
• Not checked yetcites [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
• Not checked yetcites [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
• Not checked yetcites [9] Montarras, D. et al. Direct isolation of satellite cells for skeletal muscle regeneration. Science 309, 2064–2067 (2005). source
• Not checked yetcites [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 yetcites [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
• Not checked yetcites [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

In the paper

“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.”

In the paper

“With aging, muscle tissue homeostasis is progressively disrupted and the ability of MuSCs to repair injured muscle markedly declines.”

What the sources say

• Not checked yetcites [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 yetcites [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 yetcites [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 yetcites [56] Sousa-Victor, P. et al. Geriatric muscle stem cells switch reversible quiescence into senescence. Nature 506, 316–321 (2014). source

In the paper

“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.”

What the sources say

• Not checked yetcites [1] Buchman, T.G. The community of the self. Nature 420, 246–251 (2002). source

In the paper

“MuSCs and their myogenic progeny are exposed to increased levels of circulating Wnt3a (wingless-type MMTV integration site family, member 3A) in aged mice34.”

What the sources say

• Not checked yetcites [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

In the paper

“Importantly, there are monomeric (12.5 kDa) and dimeric (25 kDa) forms of both myostatin and GDF11, which were not distinguished using the cross-reacting antibodies in these studies42,43.”

What the sources say

• Not checked yetcites [42] Sinha, M. et al. Restoring systemic GDF11 levels reverses age-related dysfunction in mouse skeletal muscle. Science 344, 649–652 (2014). source
• Not checked yetcites [43] Egerman, M.A. et al. GDF11 increases with age and inhibits skeletal muscle regeneration. Cell Metab. 22, 164–174 (2015). source

In the paper

“With these insights, we posit a new model of defective skeletal muscle repair during aging, which places the MuSC itself at the center of the progressive changes that disrupt muscle tissue homeostasis to limit stem cell self-renewal and regenerative function.”

In the paper

“The first study42 focused on the monomeric forms of GDF11 and myostatin and showed that they cumulatively decrease in abundance in serum with aging42,44.”

What the sources say

• Not checked yetcites [42] Sinha, M. et al. Restoring systemic GDF11 levels reverses age-related dysfunction in mouse skeletal muscle. Science 344, 649–652 (2014). source
• Not checked yetcites [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

In the paper

“Conversely, regeneration of muscles in young mice is impaired when exposed to an aged circulation34.”

What the sources say

• Not checked yetcites [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

In the paper

“Mature GDF11 shares 90% amino acid homology45 with myostatin (GDF8), another TGF-β superfamily member, which has a well-documented role in decreasing muscle mass and interfering with muscle repair.”

What the sources say

• Not checked yetcites [45] Nakashima, M., Toyono, T., Akamine, A. & Joyner, A. Expression of growth/differentiation factor 11, a new member of the BMP/TGFβ superfamily during mouse embryogenesis. Mech. Dev. 80, 185–189 (1999). source

In the paper

“Targeting these cell-extrinsic changes in aged mice, either through parabiosis and exposure to factors in young serum or, more directly, via ectopic activation of Notch signaling, inhibition of Wnt3a-β-catenin signaling, or oxytocin supplementation, partially restores MuSC-mediated muscle regeneration34,37,38,41.”

What the sources say

• Not checked yetcites [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 yetcites [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
• Not checked yetcites [38] Conboy, I.M., Conboy, M.J., Smythe, G.M. & Rando, T.A. Notch-mediated restoration of regenerative potential to aged muscle. Science 302, 1575–1577 (2003). source

In the paper

“Aged muscles exhibit decreased expression of the Notch ligand Delta-1 on the myofiber plasma membrane38, which normally operates to activate Notch-mediated genes that are critical for MuSC activation and self-renewal39,40.”

What the sources say

• Not checked yetcites [38] Conboy, I.M., Conboy, M.J., Smythe, G.M. & Rando, T.A. Notch-mediated restoration of regenerative potential to aged muscle. Science 302, 1575–1577 (2003). source

In the paper

“Aged muscles exhibit decreased expression of the Notch ligand Delta-1 on the myofiber plasma membrane38, which normally operates to activate Notch-mediated genes that are critical for MuSC activation and self-renewal39,40.”

What the sources say

• Not checked yetcites [39] Bjornson, C.R. et al. Notch signaling is necessary to maintain quiescence in adult muscle stem cells. Stem Cells 30, 232–242 (2012). source
• Not checked yetcites [40] Mourikis, P. et al. A critical requirement for notch signaling in maintenance of the quiescent skeletal muscle stem cell state. Stem Cells 30, 243–252 (2012). source

In the paper

“GDF11 and myostatin activate the same signaling pathways (SMAD2/3, p38 MAPK, and ERK) via the type IIB activin receptor (ActRIIB)46.”

What the sources say

• Not checked yetcites [46] Lee, S.J. Regulation of muscle mass by myostatin. Annu. Rev. Cell Dev. Biol. 20, 61–86 (2004). source

In the paper

“In parallel, cell-intrinsic alterations in signal transduction, cell cycle regulators, transcription factor profiles and epigenetic signatures are propagated through self-renewing divisions and accumulate in aged MuSCs.”

In the paper

“The regenerative function of MuSCs is regulated by their interaction with components of their extrinsic tissue microenvironment or ‘niche,’ including systemic proteins and localized structural and soluble factors that affect cell cycle and transcriptional regulation18 and alter muscle biomechanical properties and contractile forces19,20.”

What the sources say

• Not checked yetcites [18] Dumont, N.A., Wang, Y.X. & Rudnicki, M.A. Intrinsic and extrinsic mechanisms regulating satellite cell function. Development 142, 1572–1581 (2015). source
• Not checked yetcites [19] Gilbert, P.M. & Blau, H.M. Engineering a stem cell house into a home. Stem Cell Res. Ther. 2, 3 (2011). source
• Not checked yetcites [20] Yin, H., Price, F. & Rudnicki, M.A. Satellite cells and the muscle stem cell niche. Physiol. Rev. 93, 23–67 (2013). source

In the paper

“Heterochronic parabiosis experiments first suggested that factors are present in the circulation of young mice capable of rejuvenating muscle repair in aged mice.”

What the sources say

• Not checked yetcites [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 yetcites [35] Conboy, I.M. et al. Rejuvenation of aged progenitor cells by exposure to a young systemic environment. Nature 433, 760–764 (2005). source

In the paper

“Subsequently, MuSCs undergo multiple rounds of self-renewing divisions that are essential to their function in regeneration, as demonstrated by transplantation, genetic ablation, and lineage tracing experiments5–12.”

What the sources say

• Not checked yetcites [5] Bosnakovski, D. et al. Prospective isolation of skeletal muscle stem cells with a Pax7 reporter. Stem Cells 26, 3194–3204 (2008). source
• Not checked yetcites [6] Cerletti, M. et al. Highly efficient, functional engraftment of skeletal muscle stem cells in dystrophic muscles. Cell 134, 37–47 (2008). source
• Not checked yetcites [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
• Not checked yetcites [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
• Not checked yetcites [9] Montarras, D. et al. Direct isolation of satellite cells for skeletal muscle regeneration. Science 309, 2064–2067 (2005). source
• Not checked yetcites [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 yetcites [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
• Not checked yetcites [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

In the paper

“When young (2–6 months) and aged (18–26 months) mice are conjoined and their circulatory systems are shared, the muscles of aged mice in such heterochronic parabiotic pairs exhibit a more robust regenerative response to local injury than do aged mice in isochronic pairs34,35.”

What the sources say

• Not checked yetcites [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 yetcites [35] Conboy, I.M. et al. Rejuvenation of aged progenitor cells by exposure to a young systemic environment. Nature 433, 760–764 (2005). source

In the paper

“In aged mice, regenerative defects have been pinpointed as arising from signaling pathways governed by microenvironmental factors that are dysregulated in aging (Fig. 2).”

In the paper

“Grafting experiments, in which portions of intact muscle tissues are heterochronically transplanted between young and aged mice, provided the first indication that the chronological age of the muscle microenvironment exerts a profound influence on muscle regenerative capacity32.”

What the sources say

• Not checked yetcites [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

In the paper

“We propose that tissue homeostasis is fundamental to proper muscle regeneration in response to damage and is regulated by a delicate balance of temporally coordinated cellular interactions and effectors, and molecular feedback circuits in which MuSCs have a central role.”

In the paper

“For example, the Notch and Wnt pathways, which have crucial roles in muscle development and are transiently activated in the regenerative process in healthy adult muscles37, are aberrantly regulated in aged muscles.”

What the sources say

• Not checked yetcites [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

In the paper

“Remarkably, stem cells derived from primary transplants of aged MuSCs remained severely defective in their ability to engraft and repair damaged muscle tissues in secondary young recipients (Fig. 3), demonstrating that prolonged exposure to a young muscle tissue environment after transplantation is not sufficient to rejuvenate the aged MuSC population29,56.”

What the sources say

• Not checked yetcites [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 yetcites [56] Sousa-Victor, P. et al. Geriatric muscle stem cells switch reversible quiescence into senescence. Nature 506, 316–321 (2014). source

In the paper

“Remarkably, stem cells derived from primary transplants of aged MuSCs remained severely defective in their ability to engraft and repair damaged muscle tissues in secondary young recipients (Fig. 3), demonstrating that prolonged exposure to a young muscle tissue environment after transplantation is not sufficient to rejuvenate the aged MuSC population29,56.”

What the sources say

• Not checked yetcites [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 yetcites [56] Sousa-Victor, P. et al. Geriatric muscle stem cells switch reversible quiescence into senescence. Nature 506, 316–321 (2014). source

In the paper

“The cell-intrinsic dysfunction of the aged MuSC population arises from alterations in a combination of multiple signal transduction cascades, which converge on a shared set of cell cycle kinases and myogenic differentiation factors.”

What the sources say

• Not checked yetcites [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 yetcites [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 yetcites [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

In the paper

“However, these findings are based on Pax7CreER-DTA models which do not completely ablate the MuSC population.”

What the sources say

• Not checked yetcites [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 yetcites [28] Keefe, A.C. et al. Muscle stem cells contribute to myofibres in sedentary adult mice. Nat. Commun. 6, 7087 (2015). source

In the paper

“In particular, the rejuvenation of MuSCs ex vivo can be achieved by growing MuSCs on a soft hydrogel substrate with muscle-like rigidity (Figs. 3 and 4) and transient treatment with a chemical inhibitor of p38α/β MAPK 29.”

What the sources say

• Not checked yetcites [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

In the paper

“Furthermore, aberrant p38α/β activity suppresses Pax7 expression through repressive chromatin modifications57.”

What the sources say

• Not checked yetcites [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

In the paper

“Conditional ablation of Pax7-expressing MuSCs from aged muscles neither accelerates nor slows muscle wasting17,28.”

What the sources say

• Not checked yetcites [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 yetcites [28] Keefe, A.C. et al. Muscle stem cells contribute to myofibres in sedentary adult mice. Nat. Commun. 6, 7087 (2015). source

In the paper

“Indeed, sub-populations of senescent MuSCs marked by expression of p16Ink4a contribute to sarcopenic wasting and repair dysfunction characteristic of aged muscles in the accelerated-aging BubR1 hypomorphic mouse model59,60.”

What the sources say

• Not checked yetcites [59] Baker, D.J. et al. Opposing roles for p16Ink4a and p19Arf in senescence and ageing caused by BubR1 insufficiency. Nat. Cell Biol. 10, 825–836 (2008). source
• Not checked yetcites [60] Baker, D.J. et al. Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature 479, 232–236 (2011). source

In the paper

“In mouse aging, a decline in MuSC regenerative capacity is evident well before a decline in MuSC numbers is apparent.”

In the paper

“Intriguingly, adult Gdf11-null mice have no muscle defects51.”

What the sources say

• Not checked yetcites [51] McPherron, A.C., Lawler, A.M. & Lee, S.J. Regulation of anterior/posterior patterning of the axial skeleton by growth/differentiation factor 11. Nat. Genet. 22, 260–264 (1999). source

In the paper

“Depending on the ligand, p38α/β MAPK and Jak2–Stat3 signaling axes can negatively regulate MuSC self-renewal by restricting cell cycle progression and promoting myogenic differentiation through activation of commitment genes such as Myod1.”

In the paper

“A substantial fraction of MuSCs from aged and geriatric mice display a premature cellular senescence phenotype, caused by the aging-associated derepression of the cell cycle inhibitor p16Ink4a.”

What the sources say

• Not checked yetcites [56] Sousa-Victor, P. et al. Geriatric muscle stem cells switch reversible quiescence into senescence. Nature 506, 316–321 (2014). source

In the paper

“Rejuvenation of the regenerative capacity of aged and geriatric MuSC populations can be achieved by biochemical or genetic inhibition of aberrantly regulated intrinsic MuSC signal transduction pathways, including the p38α/β MAPK, and Jak2–Stat3 signaling axes25,29,55,56.”

What the sources say

• Not checked yetcites [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 yetcites [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 yetcites [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

In the paper

“Indeed MuSC numbers do not decrease appreciably until a highly advanced ‘geriatric’ age (>26 months) as determined by scoring of MuSCs in their anatomically defined niche in muscle tissue sections52,53.”

What the sources say

• Not checked yetcites [52] Brack, A.S. & Rando, T.A. Intrinsic changes and extrinsic influences of myogenic stem cell function during aging. Stem Cell Rev. 3, 226–237 (2007). source
• Not checked yetcites [53] García-Prat, L., Sousa-Victor, P. & Munoz-Canoves, P. Functional dysregulation of stem cells during aging: a focus on skeletal muscle stem cells. FEBS J. 280, 4051–4062 (2013). source

In the paper

“Moreover, the MuSC reservoir is progressively depleted by disruption of the balance of MuSC asymmetric self-renewal, leading to stem cell divisions in which both daughter cells become committed7,58.”

What the sources say

• Not checked yetcites [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
• Not checked yetcites [58] Troy, A. et al. Coordination of satellite cell activation and self-renewal by Par-complex-dependent asymmetric activation of p38alpha/beta MAPK. Cell Stem Cell 11, 541–553 (2012). source

In the paper

“These studies showed that MuSCs meet the definition of a tissue-specific stem cell as established by the hematopoiesis field54.”

What the sources say

• Not checked yetcites [54] Notta, F. et al. Isolation of single human hematopoietic stem cells capable of long-term multilineage engraftment. Science 333, 218–221 (2011). source

In the paper

“The prospective isolation methods described above enabled recent findings demonstrating that MuSCs from aged tissues accumulate intrinsic changes that lead to a reduction in self-renewal and repair capacity, relative to young tissues, when placed in equivalent in vivo repair settings22,25,29,55,56 (Fig. 3).”

What the sources say

• Not checked yetcites [22] Mauro, A. Satellite cell of skeletal muscle fibers. J. Biophys. Biochem. Cytol. 9, 493–495 (1961). source
• Not checked yetcites [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 yetcites [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

In the paper

“Although these inflammatory phases are normally transient, when these phases are not temporally coordinated, damage persists and regeneration is impaired65.”

What the sources say

• Not checked yetcites [65] Bouché, M., Munoz-Canoves, P., Rossi, F. & Coletti, D. Inflammation in muscle repair, aging, and myopathies. Biomed Res. Int. 2014, 821950 (2014). source

In the paper

“These studies showed that the timing of inflammatory responses can have profound effects on the kinetics and extent of regeneration69, findings confirmed by experiments using antibodies to block inflammatory cytokines70,71.”

What the sources say

• Not checked yetcites [69] Arnold, L. et al. Inflammatory monocytes recruited after skeletal muscle injury switch into antiinflammatory macrophages to support myogenesis. J. Exp. Med. 204, 1057–1069 (2007). source
• Not checked yetcites [70] Cheng, M., Nguyen, M.H., Fantuzzi, G. & Koh, T.J. Endogenous interferon-gamma is required for efficient skeletal muscle regeneration. Am. J. Physiol. Cell Physiol. 294, C1183–C1191 (2008). source
• Not checked yetcites [71] Perdiguero, E. et al. p38/MKP-1-regulated AKT coordinates macrophage transitions and resolution of inflammation during tissue repair. J. Cell Biol. 195, 307–322 (2011). source

In the paper

“In part, the expansion of resident FAPs is mediated by the infiltration of eosinophils that secrete IL-4, which activates FAP proliferation78.”

What the sources say

• Not checked yetcites [78] Heredia, J.E. et al. Type 2 innate signals stimulate fibro/adipogenic progenitors to facilitate muscle regeneration. Cell 153, 376–388 (2013). source

In the paper

“Accordingly, in chronic injury, accumulation of non-myogenic cell populations such as FAPs and fibroblasts disrupts muscle tissue homeostasis and impedes muscle regeneration 79,81,82.”

What the sources say

• Not checked yetcites [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
• Not checked yetcites [81] Rodeheffer, M.S. Tipping the scale: muscle versus fat. Nat. Cell Biol. 12, 102–104 (2010). source
• Not checked yetcites [82] Serrano, A.L. et al. Cellular and molecular mechanisms regulating fibrosis in skeletal muscle repair and disease. Curr. Top. Dev. Biol. 96, 167–201 (2011). source

In the paper

“Transient secretion of SASP components, such as platelet-derived growth factor A (PDGF-A) has been shown to be beneficial for tissue repair when produced by fibroblasts and endothelial cells in an acute response to skin damage74.”

What the sources say

• Not checked yetcites [74] Demaria, M. et al. An essential role for senescent cells in optimal wound healing through secretion of PDGF-AA. Dev. Cell 31, 722–733 (2014). source

In the paper

“For example, single-cell tracking by time-lapse microscopy of clonal division kinetics revealed that only a subset of aged MuSCs respond to chemical inhibition of p38α/β MAPK, not the entire population29.”

What the sources say

• Not checked yetcites [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

In the paper

“Additionally, upon damage, macrophages infiltrate muscle tissue and mediate FAP clearance by inducing apoptosis via TNF-α secretion79.”

What the sources say

• Not checked yetcites [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

In the paper

“These studies suggest that inflammatory cytokines that normally regulate muscle injury responses contribute to stem cell dysregulation and exhaustion in aged tissues.”

In the paper

“Under physiological conditions, FAPs remain quiescent but rapidly and transiently expand in response to acute muscle damage to facilitate myogenesis75 (Fig. 2).”

What the sources say

• Not checked yetcites [75] Joe, A.W. et al. Muscle injury activates resident fibro/adipogenic progenitors that facilitate myogenesis. Nat. Cell Biol. 12, 153–163 (2010). source

In the paper

“Several studies of MuSC function in muscle regeneration following injury indicate that MuSCs from aged mice (18–22 months) have stem cell–intrinsic defects25,29,55,56 (Fig. 3) that accrue before the depletion of MuSC numbers evident in geriatric mice13,56,72.”

What the sources say

• Not checked yetcites [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 yetcites [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 yetcites [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

In the paper

“Thus, alterations in ECM homeostasis can have a major impact on stem cell function in regeneration.”

In the paper

“Binding of ECM molecules to specific integrin receptors affects intracellular signaling by, for example, by triggering activation of PI3K and Rac1–MAPK pathways that induce MuSC activation and differentiation96,97.”

What the sources say

• Not checked yetcites [96] Liu, H., Niu, A., Chen, S.E. & Li, Y.P. Beta3-integrin mediates satellite cell differentiation in regenerating mouse muscle. FASEB J. 25, 1914–1921 (2011). source
• Not checked yetcites [97] Wang, H.V. et al. Integrin-linked kinase stabilizes myotendinous junctions and protects muscle from stress-induced damage. J. Cell Biol. 180, 1037–1049 (2008). source

In the paper

“Stem cell dysfunction can be caused by changes in biophysical properties, which alter cell polarity.”

In the paper

“The active TGF-β subsequently stimulates matrix deposition in several cell types within muscle tissue, including myofibroblasts, leading to increased matrix rigidity86.”

What the sources say

• Not checked yetcites [86] Philippou, A., Maridaki, M. & Koutsilieris, M. The role of urokinase-type plasminogen activator (uPA) and transforming growth factor beta 1 (TGFβ1) in muscle regeneration. In Vivo 22, 735–750 (2008).

In the paper

“These factors can derive from the circulation or neighboring cell types such as FAPs, fibroblasts and immune cells, as discussed herein, and other cell types which also play important roles, including adipocytes, endothelial cells, mesoangioblasts, PW1+ interstitial cells and myofibroblasts109–111.”

What the sources say

• Not checked yetcites [109] Paylor, B., Natarajan, A., Zhang, R.H. & Rossi, F. Nonmyogenic cells in skeletal muscle regeneration. Curr. Top. Dev. Biol. 96, 139–165 (2011). source
• Not checked yetcites [110] Bentzinger, C.F., Wang, Y.X., Dumont, N.A. & Rudnicki, M.A. Cellular dynamics in the muscle satellite cell niche. EMBO Rep. 14, 1062–1072 (2013). source
• Not checked yetcites [111] Bonfanti, C. et al. PW1/Peg3 expression regluates key properties that determine mesoangioblast stem cell competence. Nat. Commun. 6, 6364 (2015). source

In the paper

“Specific examples include a complex of Pax7 to the histone methyltransferases ASH2L and MLL, which activates a number of myogenic genes108.”

What the sources say

• Not checked yetcites [108] McKinnell, I.W. et al. Pax7 activates myogenic genes by recruitment of a histone methyltransferase complex. Nat. Cell Biol. 10, 77–84 (2008). source

In the paper

“The Par3 complex mediates asymmetric segregation of MuSCs with active (phosphorylated) and inactive p38α/β MAPK, which yields committed and uncommitted daughter cells55,58.”

What the sources say

• Not checked yetcites [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 yetcites [58] Troy, A. et al. Coordination of satellite cell activation and self-renewal by Par-complex-dependent asymmetric activation of p38alpha/beta MAPK. Cell Stem Cell 11, 541–553 (2012). source

In the paper

“Exposure of multipotent mesenchymal stem cells to such changes in biophysical properties of substrates triggered altered gene expression typical of myogenic, chondrogenic, adipogenic, and osteogenic cell types101.”

What the sources say

• Not checked yetcites [101] Engler, A.J., Sen, S., Sweeney, H.L. & Discher, D.E. Matrix elasticity directs stem cell lineage specification. Cell 126, 677–689 (2006). source

In the paper

“For example, IL-6–mediated induction of MMP9 (ref. 84) converts the matrix-tethered latent TGF-β complex to an active form 85.”

What the sources say

• Not checked yetcites [84] Kothari, P. et al. IL-6-mediated induction of matrix metalloproteinase-9 is modulated by JAK-dependent IL-10 expression in macrophages. J. Immunol. 192, 349–357 (2014). source
• Not checked yetcites [85] Yu, Q. & Stamenkovic, I. Cell surface-localized matrix metalloproteinase-9 proteolytically activates TGF-β and promotes tumor invasion and angiogenesis. Genes Dev. 14, 163–176 (2000). source

In the paper

“As many as 1,800 genes are associated with repressive H3K4me3 and H3K27me3 epigenetic marks in aged mouse muscles107.”

What the sources say

• Not checked yetcites [107] Liu, L. et al. Chromatin modifications as determinants of muscle stem cell quiescence and chronological aging. Cell Rep 4, 189–204 (2013). source

In the paper

“By contrast, if the matrix is synthesized to mimic the rigidity of muscle tissue (five orders of magnitude less stiff), stem cell function is retained, as shown by transplantation of young MuSCs after culture on soft hydrogels (12 kPa)31.”

What the sources say

• Not checked yetcites [31] Gilbert, P.M. et al. Substrate elasticity regulates skeletal muscle stem cell self-renewal in culture. Science 329, 1078–1081 (2010). source

In the paper

“These alterations are commensurate with changes in the ability of the myofiber ECM to retain glycoproteins such as osteopontin, which bind heparan sulfate and other proteoglycans91.”

What the sources say

• Not checked yetcites [91] Paliwal, P., Pishesha, N., Wijaya, D. & Conboy, I.M. Age dependent increase in the levels of osteopontin inhibits skeletal muscle regeneration. Aging (Albany, NY) 4, 553–566 (2012). source

In the paper

“These changes lead to a more rigid tissue microenvironment92,93.”

What the sources say

• Not checked yetcites [92] Rosant, C., Nagel, M.D. & Perot, C. Aging affects passive stiffness and spindle function of the rat soleus muscle. Exp. Gerontol. 42, 301–308 (2007). source
• Not checked yetcites [93] Gao, Y., Kostrominova, T.Y., Faulkner, J.A. & Wineman, A.S. Age-related changes in the mechanical properties of the epimysium in skeletal muscles of rats. J. Biomech. 41, 465–469 (2008). source

In the paper

“The underlying mechanisms for these cell fate changes may include epigenetic modifications.”

In the paper

“During muscle development, growth, and regeneration, there is a dynamic balance of remodeling enzymes such as matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs), which control the integrity of the ECM83.”

What the sources say

• Not checked yetcites [83] Thorsteinsdóttir, S., Deries, M., Cachaco, A.S. & Bajanca, F. The extracellular matrix dimension of skeletal muscle development. Dev. Biol. 354, 191–207 (2011). source

In the paper

“Furthermore, such protein composition changes could account for biomechanical changes to the myofiber basal lamina and muscle epimysium that have been shown to accompany aging.”

In the paper

“A shift in this delicate balance of temporally coordinated cell types and regulators with aging could lead to MuSC malfunction and defective regeneration.”

In the paper

“Apical-basal polarity cues orient the mitotic spindle perpendicular to the basement membrane (in skin and gut epithelium) or basal lamina (in muscle fibers) to induce asymmetric stem cell division, leading to the generation of a daughter cell that proliferates and one that remains quiescent7,105,106.”

What the sources say

• Not checked yetcites [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
• Not checked yetcites [105] Lechler, T. & Fuchs, E. Asymmetric cell divisions promote stratification and differentiation of mammalian skin. Nature 437, 275–280 (2005). source
• Not checked yetcites [106] Quyn, A.J. et al. Spindle orientation bias in gut epithelial stem cell compartments is lost in precancerous tissue. Cell Stem Cell 6, 175–181 (2010). source

In the paper

“The findings from serial transplantation experiments show that aged MuSCs have a persistent impairment—a “memory” that is inherited in their progeny (Fig. 3).”

In the paper

“However, the cumulative exposure to these factors over an organism's lifetime alters the MuSC-intrinsic capacity to regenerate muscle damage.”