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p38 MAPK signaling underlies a cell-autonomous loss of stem cell self-renewal in skeletal muscle of aged mice

Abstract

Skeletal muscle aging results in a gradual loss of skeletal muscle mass, skeletal muscle function and regenerative capacity, which can lead to sarcopenia and increased mortality. Although the mechanisms underlying sarcopenia remain unclear, the skeletal muscle stem cell, or satellite cell, is required for muscle regeneration. Therefore, identification of signaling pathways affecting satellite cell function during aging may provide insights into therapeutic targets for combating sarcopenia. Here, we show that a cell-autonomous loss in self-renewal occurs via alterations in fibroblast growth factor receptor-1, p38α and p38β mitogen-activated protein kinase signaling in satellite cells from aged mice. We further demonstrate that pharmacological manipulation of these pathways can ameliorate age-associated self-renewal defects. Thus, our data highlight an age-associated deregulation of a satellite cell homeostatic network and reveal potential therapeutic opportunities for the treatment of progressive muscle wasting.

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Figure 1: Heterochronic transplantation of SCs from aged mice to local or systemic young environment fails to rescue age-associated phenotypes.
Figure 2: Loss of self-renewal in SCs from aged mice correlates with elevated p38 signaling.
Figure 3: Partial inhibition of p38α/β MAPK rescues aged SCs self-renewal.
Figure 4: FGFR1 signaling is altered in SCs from aged mice compared to those from young mice.
Figure 5: Constitutive FGFR1 signaling partially rescues self-renewal in SCs from aged mice.
Figure 6: Partial p38α/β MAPK inhibition rescues the engraftment of SCs from aged mice.

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References

  1. Evans, W.J. & Campbell, W.W. Sarcopenia and age-related changes in body composition and functional capacity. J. Nutr. 123, 465–468 (1993).

    Article  CAS  Google Scholar 

  2. Baumgartner, R.N. et al. Epidemiology of sarcopenia among the elderly in New Mexico. Am. J. Epidemiol. 147, 755–763 (1998).

    Article  CAS  Google Scholar 

  3. Roubenoff, R. Sarcopenia: a major modifiable cause of frailty in the elderly: Sarcopenia in aging. J. Nutr. Health Aging 4, 140–142 (2000).

    CAS  PubMed  Google Scholar 

  4. Landi, F. et al. Sarcopenia and mortality risk in frail older persons aged 80 years and older: results from ilSIRENTE study. Age Ageing 42, 203–209 (2013).

    Article  Google Scholar 

  5. Janssen, I., Shepard, D.S., Katzmarzyk, P.T. & Roubenoff, R. The healthcare costs of sarcopenia in the United States. J. Am. Geriatr. Soc. 52, 80–85 (2004).

    Article  Google Scholar 

  6. Brooks, S.V. & Faulkner, J.A. Contraction-induced injury: recovery of skeletal muscles in young and old mice. Am. J. Physiol. 258, C436–C442 (1990).

    Article  CAS  Google Scholar 

  7. Grounds, M.D. Age-associated changes in the response of skeletal muscle cells to exercise and regeneration. Ann. NY Acad. Sci. 854, 78–91 (1998).

    Article  CAS  Google Scholar 

  8. Karakelides, H. & Nair, K.S. Sarcopenia of aging and its metabolic impact. Curr. Top. Dev. Biol. 68, 123–148 (2005).

    Article  CAS  Google Scholar 

  9. Day, K., Shefer, G., Shearer, A. & Yablonka-Reuveni, Z. The depletion of skeletal muscle satellite cells with age is concomitant with reduced capacity of single progenitors to produce reserve progeny. Dev. Biol. 340, 330–343 (2010).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  12. Lepper, C., Partridge, T.A. & Fan, C.M. An absolute requirement for Pax7-positive satellite cells in acute injury-induced skeletal muscle regeneration. Development 138, 3639–3646 (2011).

    Article  CAS  Google Scholar 

  13. 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  Google Scholar 

  14. Sadeh, M. Effects of aging on skeletal muscle regeneration. J. Neurol. Sci. 87, 67–74 (1988).

    Article  CAS  Google Scholar 

  15. McGeachie, J.K. & Grounds, M. Retarded myogenic cell replication in regenerating skeletal muscles of old mice: an autoradiographic study in young and old BALBc and SJL/J mice. Cell Tissue Res. 280, 277–282 (1995).

    Article  CAS  Google Scholar 

  16. Marsh, D.R., Criswell, D.S., Carson, J.A. & Booth, F.W. Myogenic regulatory factors during regeneration of skeletal muscle in young, adult, and old rats. J. Appl. Physiol. 83, 1270–1275 (1997).

    Article  CAS  Google Scholar 

  17. 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  Google Scholar 

  18. 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  Google Scholar 

  19. 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  Google Scholar 

  20. Carlson, B.M. & Faulkner, J.A. The Regeneration of Noninnervated Musele Grafts and Marcaine-Treated Muscles in Young and Old Rats. J. Gerontol. A Biol. Sci. Med. Sci. 51, B43–B49 (1996).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  22. 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  Google Scholar 

  23. 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  Google Scholar 

  24. Hannon, K., Kudla, A.J., McAvoy, M.J., Clase, K.L. & Olwin, B.B. Differentially expressed fibroblast growth factors regulate skeletal muscle development through autocrine and paracrine mechanisms. J. Cell Biol. 132, 1151–1159 (1996).

    Article  CAS  Google Scholar 

  25. Sheehan, S.M. & Allen, R.E. Skeletal muscle satellite cell proliferation in response to members of the fibroblast growth factor family and hepatocyte growth factor. J. Cell. Physiol. 181, 499–506 (1999).

    Article  CAS  Google Scholar 

  26. Kudla, A.J. et al. The FGF receptor-1 tyrosine kinase domain regulates myogenesis but is not sufficient to stimulate proliferation. J. Cell Biol. 142, 241–250 (1998).

    Article  CAS  Google Scholar 

  27. Flanagan-Steet, H., Hannon, K., McAvoy, M.J., Hullinger, R. & Olwin, B.B. Loss of FGF receptor 1 signaling reduces skeletal muscle mass and disrupts myofiber organization in the developing limb. Dev. Biol. 218, 21–37 (2000).

    Article  CAS  Google Scholar 

  28. Kästner, S., Elias, M.C., Rivera, A.J. & Yablonka-Reuveni, Z. Gene expression patterns of the fibroblast growth factors and their receptors during myogenesis of rat satellite cells. J. Histochem. Cytochem. 48, 1079–1096 (2000).

    Article  Google Scholar 

  29. Lagha, M. et al. Pax3 regulation of FGF signaling affects the progression of embryonic progenitor cells into the myogenic program. Genes Dev. 22, 1828–1837 (2008).

    Article  CAS  Google Scholar 

  30. Jones, N.C., Fedorov, Y.V., Rosenthal, R.S. & Olwin, B.B. ERK1/2 is required for myoblast proliferation but is dispensable for muscle gene expression and cell fusion. J. Cell. Physiol. 186, 104–115 (2001).

    Article  CAS  Google Scholar 

  31. Jones, N.C. et al. The p38alpha/beta MAPK functions as a molecular switch to activate the quiescent satellite cell. J. Cell Biol. 169, 105–116 (2005).

    Article  CAS  Google Scholar 

  32. 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  Google Scholar 

  33. Troy, A. et al. Coordination of Satellite Cell Activation and Self-Renewal by Par-Complex-Dependent Asymmetric Activation of p38α/β MAPK. Cell Stem Cell 11, 541–553 (2012).

    Article  CAS  Google Scholar 

  34. Kang, J.S. et al. A Cdo-Bnip-2-Cdc42 signaling pathway regulates p38alpha/beta MAPK activity and myogenic differentiation. J. Cell Biol. 182, 497–507 (2008).

    Article  CAS  Google Scholar 

  35. Gillespie, M.A. et al. p38-gamma-dependent gene silencing restricts entry into the myogenic differentiation program. J. Cell Biol. 187, 991–1005 (2009).

    Article  CAS  Google Scholar 

  36. Shefer, G., Van de Mark, D.P., Richardson, J.B. & Yablonka-Reuveni, Z. Satellite-cell pool size does matter: defining the myogenic potency of aging skeletal muscle. Dev. Biol. 294, 50–66 (2006).

    Article  CAS  Google Scholar 

  37. 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  Google Scholar 

  38. Whitney, M.L., Otto, K.G., Blau, C.A., Reinecke, H. & Murry, C.E. Control of myoblast proliferation with a synthetic ligand. J. Biol. Chem. 276, 41191–41196 (2001).

    Article  CAS  Google Scholar 

  39. Stevens, K.R. et al. Chemical dimerization of fibroblast growth factor receptor-1 induces myoblast proliferation, increases intracardiac graft size, and reduces ventricular dilation in infarcted hearts. Hum. Gene Ther. 18, 401–412 (2007).

    Article  CAS  Google Scholar 

  40. Faulkner, J.A., Larkin, L.M., Claflin, D.R. & Brooks, S.V. Age-related changes in the structure and function of skeletal muscles. Clin. Exp. Pharmacol. Physiol. 34, 1091–1096 (2007).

    Article  CAS  Google Scholar 

  41. Rüegg, M.A. & Glass, D.J. Molecular mechanisms and treatment options for muscle wasting diseases. Annu. Rev. Pharmacol. Toxicol. 51, 373–395 (2011).

    Article  Google Scholar 

  42. Brien, P., Pugazhendhi, D., Woodhouse, S., Oxley, D. & Pell, J.M. P38α MAPK regulates adult muscle stem cell fate by restricting progenitor proliferation during postnatal growth and repair. Stem Cells 31, 1597–1610 (2013).

    Article  CAS  Google Scholar 

  43. Cornelison, D.D. et al. Essential and separable roles for Syndecan-3 and Syndecan-4 in skeletal muscle development and regeneration. Genes Dev. 18, 2231–2236 (2004).

    Article  CAS  Google Scholar 

  44. Yayon, A., Klagsbrun, M., Esko, J., Leder, P. & Ornitz, D. Cell surface, heparin-like molecules are required for binding of basic fibroblast growth factor to its high affinity receptor. Cell 64, 841–848 (1991).

    Article  CAS  Google Scholar 

  45. Rapraeger, A.C., Krufka, A. & Olwin, B.B. Requirement of heparan sulfate for bFGF-mediated fibroblast growth and myoblast differentiation. Science 252, 1705–1708 (1991).

    Article  CAS  Google Scholar 

  46. Schlessinger, J. et al. Crystal structure of a ternary FGF-FGFR-heparin complex reveals a dual role for heparin in FGFR binding and dimerization. Mol. Cell 6, 743–750 (2000).

    Article  CAS  Google Scholar 

  47. Huynh, M.B. et al. Age-related changes in rat myocardium involve altered capacities of glycosaminoglycans to potentiate growth factor functions and heparan sulfate-altered sulfation. J. Biol. Chem. 287, 11363–11373 (2012).

    Article  CAS  Google Scholar 

  48. Williamson, K.A. et al. Age-related impairment of endothelial progenitor cell migration correlates with structural alterations of heparan sulfate proteoglycans. Aging Cell 12, 139–147 (2013).

    Article  CAS  Google Scholar 

  49. Welm, B.E. et al. Inducible dimerization of FGFR1 development of a mouse model to analyze progressive transformation of the mammary gland. J. Cell Biol. 157, 703–714 (2002).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank the Olwin lab members, especially B. Pawlikowski, M. Hall and A. Cadwallader, for revising the manuscript and helpful discussions. We thank T. Vogler, T. McClure and M. Palmer for technical assistance. N. Dalla Betta helped with mouse maintenance. C. English and the University of Colorado Boulder Molecular, Cellular and Developmental Biology Light Microscopy Core provided facilities and assistance. D.M. Spencer developed the inducible FGFR1 construct available from Addgene. This work was supported by grants from the US National Institutes of Health (AR49446 and AG040074) and The Ellison Medical Foundation to B.B.O. and from the National Institutes of Health (T32GM007135) to J.D.B.

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J.D.B. and B.B.O. conceptualized the study. J.D.B. performed and analyzed the experiments. J.K.H. assisted with transplantation experiments. K.K.T. designed and performed the collection of microarray data. J.D.D. performed the microarray analysis. T.A.C. assisted with image scoring. J.D.B., B.B.O. and J.D.D. wrote, discussed and edited the manuscript. B.B.O. supervised the project.

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Correspondence to Bradley B Olwin.

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Phospho-p38αβ MAPK is asymmetrically localized across satellite cell.

Three-dimensional rendering of a myofiber-associated satellite cell at 24 h after isolation. DAPI (blue), syndecan-4 (red) and phospho-p38 (green). Syndecan-4 cell is a myonucleus. (AVI 2682 kb)

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Bernet, J., Doles, J., Hall, J. 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). https://doi.org/10.1038/nm.3465

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