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

Nature Medicine volume 21, pages 854–862 (2015)Cite this article

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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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Figure 1: The role of MuSCS in tissue homeostasis with aging.

Debbie Maizels/Nature Publishing Group

Figure 2: Extrinsic and intrinsic regulators of MuSC function are altered in aging.

Debbie Maizels/Nature Publishing Group

Figure 3: Evidence in support of intrinsic 'memory' in aged and rejuvenated MuSC populations.

Debbie Maizels/Nature Publishing Group

Figure 4: Biophysical regulation of muscle stem cells in aging.

Debbie Maizels/Nature Publishing Group

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References

  1. Buchman, T.G. The community of the self. Nature 420, 246–251 (2002).

    Article  CAS  PubMed  Google Scholar 

  2. Seale, P., Asakura, A. & Rudnicki, M.A. The potential of muscle stem cells. Dev. Cell 1, 333–342 (2001).

    Article  CAS  PubMed  Google Scholar 

  3. Cheung, T.H. & Rando, T.A. Molecular regulation of stem cell quiescence. Nat. Rev. Mol. Cell Biol. 14, 329–340 (2013).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  5. Bosnakovski, D. et al. Prospective isolation of skeletal muscle stem cells with a Pax7 reporter. Stem Cells 26, 3194–3204 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  18. Dumont, N.A., Wang, Y.X. & Rudnicki, M.A. Intrinsic and extrinsic mechanisms regulating satellite cell function. Development 142, 1572–1581 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Gilbert, P.M. & Blau, H.M. Engineering a stem cell house into a home. Stem Cell Res. Ther. 2, 3 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Yin, H., Price, F. & Rudnicki, M.A. Satellite cells and the muscle stem cell niche. Physiol. Rev. 93, 23–67 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Cornelison, D.D., Filla, M.S., Stanley, H.M., Rapraeger, A.C. & Olwin, B.B. Syndecan-3 and syndecan-4 specifically mark skeletal muscle satellite cells and are implicated in satellite cell maintenance and muscle regeneration. Dev. Biol. 239, 79–94 (2001).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Kuang, S., Gillespie, M.A. & Rudnicki, M.A. Niche regulation of muscle satellite cell self-renewal and differentiation. Cell Stem Cell 2, 22–31 (2008).

    Article  CAS  PubMed  Google Scholar 

  24. Fukada, S. et al. Molecular signature of quiescent satellite cells in adult skeletal muscle. Stem Cells 25, 2448–2459 (2007).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Nishijo, K. et al. Biomarker system for studying muscle, stem cells, and cancer in vivo. FASEB J. 23, 2681–2690 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Keefe, A.C. et al. Muscle stem cells contribute to myofibres in sedentary adult mice. Nat. Commun. 6, 7087 (2015).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Cosgrove, B.D., Sacco, A., Gilbert, P.M. & Blau, H.M. A home away from home: challenges and opportunities in engineering in vitro muscle satellite cell niches. Differentiation 78, 185–194 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  33. Carlson, B.M., Dedkov, E.I., Borisov, A.B. & Faulkner, J.A. Skeletal muscle regeneration in very old rats. J. Gerontol. A Biol. Sci. Med. Sci. 56, B224–B233 (2001).

    Article  CAS  PubMed  Google Scholar 

  34. Brack, A.S. et al. Increased Wnt signaling during aging alters muscle stem cell fate and increases fibrosis. Science 317, 807–810 (2007).

    Article  CAS  PubMed  Google Scholar 

  35. Conboy, I.M. et al. Rejuvenation of aged progenitor cells by exposure to a young systemic environment. Nature 433, 760–764 (2005).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  39. Bjornson, C.R. et al. Notch signaling is necessary to maintain quiescence in adult muscle stem cells. Stem Cells 30, 232–242 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  42. Sinha, M. et al. Restoring systemic GDF11 levels reverses age-related dysfunction in mouse skeletal muscle. Science 344, 649–652 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Egerman, M.A. et al. GDF11 increases with age and inhibits skeletal muscle regeneration. Cell Metab. 22, 164–174 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  46. Lee, S.J. Regulation of muscle mass by myostatin. Annu. Rev. Cell Dev. Biol. 20, 61–86 (2004).

    Article  CAS  PubMed  Google Scholar 

  47. Lee, S.J. et al. Regulation of muscle mass by follistatin and activins. Mol. Endocrinol. 24, 1998–2008 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. McPherron, A.C. & Lee, S.J. Double muscling in cattle due to mutations in the myostatin gene. Proc. Natl. Acad. Sci. USA 94, 12457–12461 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Kambadur, R., Sharma, M., Smith, T.P. & Bass, J.J. Mutations in myostatin (GDF8) in double-muscled Belgian Blue and Piedmontese cattle. Genome Res. 7, 910–916 (1997).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  54. Notta, F. et al. Isolation of single human hematopoietic stem cells capable of long-term multilineage engraftment. Science 333, 218–221 (2011).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Baker, D.J. et al. Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature 479, 232–236 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  65. Bouché, M., Munoz-Canoves, P., Rossi, F. & Coletti, D. Inflammation in muscle repair, aging, and myopathies. Biomed Res. Int. 2014, 821950 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

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

    PubMed  Google Scholar 

  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).

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Collins, C.A., Zammit, P.S., Ruiz, A.P., Morgan, J.E. & Partridge, T.A. A population of myogenic stem cells that survives skeletal muscle aging. Stem Cells 25, 885–894 (2007).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  PubMed  CAS  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Joe, A.W. et al. Muscle injury activates resident fibro/adipogenic progenitors that facilitate myogenesis. Nat. Cell Biol. 12, 153–163 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  78. Heredia, J.E. et al. Type 2 innate signals stimulate fibro/adipogenic progenitors to facilitate muscle regeneration. Cell 153, 376–388 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Rodeheffer, M.S. Tipping the scale: muscle versus fat. Nat. Cell Biol. 12, 102–104 (2010).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  83. Thorsteinsdóttir, S., Deries, M., Cachaco, A.S. & Bajanca, F. The extracellular matrix dimension of skeletal muscle development. Dev. Biol. 354, 191–207 (2011).

    Article  PubMed  CAS  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  PubMed  CAS  Google Scholar 

  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).

    Article  CAS  PubMed Central  Google Scholar 

  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).

    Article  PubMed  Google Scholar 

  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).

    Article  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Urciuolo, A. et al. Collagen VI regulates satellite cell self-renewal and muscle regeneration. Nat. Commun. 4, 1964 (2013).

    Article  PubMed  CAS  Google Scholar 

  100. Bentzinger, C.F. et al. Fibronectin regulates Wnt7a signaling and satellite cell expansion. Cell Stem Cell 12, 75–87 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Engler, A.J., Sen, S., Sweeney, H.L. & Discher, D.E. Matrix elasticity directs stem cell lineage specification. Cell 126, 677–689 (2006).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  103. Dupont, S. et al. Role of YAP/TAZ in mechanotransduction. Nature 474, 179–183 (2011).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Lechler, T. & Fuchs, E. Asymmetric cell divisions promote stratification and differentiation of mammalian skin. Nature 437, 275–280 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  107. Liu, L. et al. Chromatin modifications as determinants of muscle stem cell quiescence and chronological aging. Cell Rep 4, 189–204 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. McKinnell, I.W. et al. Pax7 activates myogenic genes by recruitment of a histone methyltransferase complex. Nat. Cell Biol. 10, 77–84 (2008).

    Article  CAS  PubMed  Google Scholar 

  109. Paylor, B., Natarajan, A., Zhang, R.H. & Rossi, F. Nonmyogenic cells in skeletal muscle regeneration. Curr. Top. Dev. Biol. 96, 139–165 (2011).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Bonfanti, C. et al. PW1/Peg3 expression regluates key properties that determine mesoangioblast stem cell competence. Nat. Commun. 6, 6364 (2015).

    Article  CAS  PubMed  Google Scholar 

  112. Campisi, J. Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors. Cell 120, 513–522 (2005).

    Article  CAS  PubMed  Google Scholar 

  113. Discher, D.E., Mooney, D.J. & Zandstra, P.W. Growth factors, matrices, and forces combine and control stem cells. Science 324, 1673–1677 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Paszek, M.J. et al. Tensional homeostasis and the malignant phenotype. Cancer Cell 8, 241–254 (2005).

    Article  CAS  PubMed  Google Scholar 

  115. Humphrey, J.D., Dufresne, E.R. & Schwartz, M.A. Mechanotransduction and extracellular matrix homeostasis. Nat. Rev. Mol. Cell Biol. 15, 802–812 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We apologize to those investigators whose important work we were unable to cite or describe in depth owing to the limited scope and space constraints of this Perspective. We are grateful for support from Muscular Dystrophy Association grant 217821 (A.T.V.H.); support from the US National Institutes of Health (NIH) grant R00AG042491 (B.D.C.); and The Baxter Foundation, California Institute for Regenerative Medicine (CIRM) grants RB5-07469 and TR3-05501, and NIH grants AR063963, AG020961, AG044815, and NS089533 (H.M.B.).

Author information

Author notes

  1. Benjamin D Cosgrove and Andrew T V Ho: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Microbiology and Immunology, Baxter Laboratory for Stem Cell Biology, and Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California, USA

    Helen M Blau & Andrew T V Ho

  2. Meinig School of Biomedical Engineering, Cornell University, Ithaca, New York, USA

    Benjamin D Cosgrove

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  1. Helen M Blau
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  2. Benjamin D Cosgrove
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  3. Andrew T V Ho
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Correspondence to Helen M Blau.

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Blau, H., Cosgrove, B. & Ho, A. The central role of muscle stem cells in regenerative failure with aging. Nat Med 21, 854–862 (2015). https://doi.org/10.1038/nm.3918

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