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

In the paper

“Together, these dysregulated signals impair MuSC-mediated myofiber repair and stem cell self-renewal in aged tissues and lead to the generation of fibroblasts34.”

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

“This dimeric form was not assessed in the original study44.”

What the sources say

• 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

“In addition, in young adult mice, the hormone oxytocin promotes muscle regeneration, whereas in aged mice this hormone declines41.”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

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

In the paper

“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.”

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

“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.”

What the sources say

• Not checked yetcites [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 yetcites [14] Sambasivan, R. et al. Pax7-expressing satellite cells are indispensable for adult skeletal muscle regeneration. Development 138, 3647–3656 (2011). source
• Not checked yetcites [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 yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [2] Seale, P., Asakura, A. & Rudnicki, M.A. The potential of muscle stem cells. Dev. Cell 1, 333–342 (2001). source

In the paper

“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.”

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“The second study43 confirmed this observation, but also examined the active and more abundant dimeric forms and showed that they cumulatively increase with aging.”

What the sources say

• 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

“Wnt3a stimulates β-catenin signaling, which induces undesirable fibrogenic differentiation of muscle stem and progenitor cells34, and also antagonizes Notch signaling37.”

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

In the paper

“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.”

What the sources say

• Not checked yetcites [3] Cheung, T.H. & Rando, T.A. Molecular regulation of stem cell quiescence. Nat. Rev. Mol. Cell Biol. 14, 329–340 (2013). source
• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [47] Lee, S.J. et al. Regulation of muscle mass by follistatin and activins. Mol. Endocrinol. 24, 1998–2008 (2010). source
• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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 yetcites [14] Sambasivan, R. et al. Pax7-expressing satellite cells are indispensable for adult skeletal muscle regeneration. Development 138, 3647–3656 (2011). source
• Not checked yetcites [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

In the paper

“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.”

In the paper

“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.”

What the sources say

• 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

In the paper

“Cumulatively, these cell autonomous alterations limit MuSC self-renewal and capacity for regeneration25,29,55,56.”

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

“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.”

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, 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.”

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

“Conditional ablation of this p16Ink4a-expressing MuSC population and other senescent cells ameliorates muscle wasting, leading to improved performance in treadmill exercise tests60.”

What the sources say

• 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

“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.”

In the paper

“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).”

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

“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).”

What the sources say

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

In the paper

“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.”

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
• 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

“These findings suggest that altering the function or phenotype of MuSCs in aged muscle tissue will enhance muscle repair29 and may also ameliorate sarcopenia61.”

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 [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

In the paper

“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).”

What the sources say

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

“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).”

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
• Not checked yetcites [66] Tidball, J.G. Mechanisms of muscle injury, repair, and regeneration. Compr. Physiol. 1, 2029–2062 (2011). source

In the paper

“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.”

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

“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.”

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

“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).”

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

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

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

In the paper

“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.”

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

“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).”

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

“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.”

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“Thus, although a transient inflammatory response is beneficial to regeneration, the persistent inflammation that is characteristic of chronic muscle disease impedes regeneration65.”

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

“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.”

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, 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.”

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

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

In the paper

“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).”

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
• Not checked yetcites [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 yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

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

In the paper

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

In the paper

“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.”

What the sources say

• Not checked yetcites [103] Dupont, S. et al. Role of YAP/TAZ in mechanotransduction. Nature 474, 179–183 (2011). source
• Not checked yetcites [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

In the paper

“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.”

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

“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.”

In the paper

“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.”

In the paper

“The normally laminin-rich myofiber ECM shifts toward a composition enhanced in collagen IV (refs. 88,89), but with reduced collagen VI levels90.”

What the sources say

• Not checked yetcites [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 yetcites [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 yetcites [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

In the paper

“Fibronectin binding to the Syndecan4/Frizzled complex disrupts the asymmetric self-renewal of MuSCs, thereby promoting Wnt7a-mediated symmetrical muscle stem cell expansion100.”

What the sources say

• Not checked yetcites [100] Bentzinger, C.F. et al. Fibronectin regulates Wnt7a signaling and satellite cell expansion. Cell Stem Cell 12, 75–87 (2013). source

In the paper

“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.”

In the paper

“The maintenance of MuSC self-renewal function relies heavily on rigidity, as when plated on traditional plastic dishes, stem cell function is lost.”

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

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

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

“In contrast, much softer or more rigid substrates result in a loss of MuSCs owing to decreased survival or increased myogenic commitment31.”

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

“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).”

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 [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 yetcites [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 yetcites [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

In the paper

“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,”

What the sources say

• Not checked yetcites [100] Bentzinger, C.F. et al. Fibronectin regulates Wnt7a signaling and satellite cell expansion. Cell Stem Cell 12, 75–87 (2013). source

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“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).”

In the paper

“Syndecan3, a transmembrane heparan sulfate proteoglycan (HSPG) facilitates Notch activation, which promotes MuSC self renewal and inhibits differentiation98.”

What the sources say

• Not checked yetcites [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

In the paper

“Perturbations in the FGFR–p38 signaling axis that arise in aging disrupt this asymmetric division mechanism, leading to an increase in symmetrically committed cells55.”

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

In the paper

“Collagen VI increases satellite cell numbers and promotes regeneration99.”

What the sources say

• Not checked yetcites [99] Urciuolo, A. et al. Collagen VI regulates satellite cell self-renewal and muscle regeneration. Nat. Commun. 4, 1964 (2013). source

In the paper

“MuSCs are not a homogeneous population even in young mice, and MuSC heterogeneity increases during aging14,16,25,29,56,62–64.”

What the sources say

• Not checked yetcites [14] Sambasivan, R. et al. Pax7-expressing satellite cells are indispensable for adult skeletal muscle regeneration. Development 138, 3647–3656 (2011). source
• Not checked yetcites [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 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 [56] Sousa-Victor, P. et al. Geriatric muscle stem cells switch reversible quiescence into senescence. Nature 506, 316–321 (2014). source
• Not checked yetcites [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 yetcites [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 yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [112] Campisi, J. Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors. Cell 120, 513–522 (2005). source

In the paper

“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;”

In the paper

“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.”

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
• 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