Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

STAT3 signaling controls satellite cell expansion and skeletal muscle repair

Abstract

The progressive loss of muscle regenerative capacity with age or disease results in part from a decline in the number and function of satellite cells, the direct cellular contributors to muscle repair1,2,3,4,5,6,7,8,9,10,11. However, little is known about the molecular effectors underlying satellite cell impairment and depletion. Elevated levels of inflammatory cytokines, including interleukin-6 (IL-6), are associated with both age-related and muscle-wasting conditions12,13,14,15. The levels of STAT3, a downstream effector of IL-6, are also elevated with muscle wasting16,17, and STAT3 has been implicated in the regulation of self-renewal and stem cell fate in several tissues18,19,20,21. Here we show that IL-6–activated Stat3 signaling regulates satellite cell behavior, promoting myogenic lineage progression through myogenic differentiation 1 (Myod1) regulation. Conditional ablation of Stat3 in Pax7-expressing satellite cells resulted in their increased expansion during regeneration, but compromised myogenic differentiation prevented the contribution of these cells to regenerating myofibers. In contrast, transient Stat3 inhibition promoted satellite cell expansion and enhanced tissue repair in both aged and dystrophic muscle. The effects of STAT3 inhibition on cell fate and proliferation were conserved in human myoblasts. The results of this study indicate that pharmacological manipulation of STAT3 activity can be used to counteract the functional exhaustion of satellite cells in pathological conditions, thereby maintaining the endogenous regenerative response and ameliorating muscle-wasting diseases.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Stat3 promotes myogenic lineage progression in cultured satellite cells.
Figure 2: Stat3 gene deletion enhances satellite cell expansion after skeletal muscle injury.
Figure 3: Transient inhibition of Stat3 promotes satellite cell expansion and enhances skeletal muscle tissue repair.
Figure 4: The effects of STAT3 manipulation are conserved in human myoblasts.

References

  1. Seale, P. et al. Pax7 is required for the specification of myogenic satellite cells. Cell 102, 777–786 (2000).

    Article  CAS  PubMed  Google Scholar 

  2. Collins, C.A. et al. Stem cell function, self-renewal, and behavioral heterogeneity of cells from the adult muscle satellite cell niche. Cell 122, 289–301 (2005).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  4. 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 

  5. 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 

  6. Sacco, A. et al. Short telomeres and stem cell exhaustion model Duchenne muscular dystrophy in mdx/mTR mice. Cell 143, 1059–1071 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. 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  PubMed  PubMed Central  Google Scholar 

  8. 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 

  9. 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 

  10. 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 

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

    Article  CAS  PubMed  Google Scholar 

  12. Tidball, J.G. Inflammatory processes in muscle injury and repair. Am. J. Physiol. Regul. Integr. Comp. Physiol. 288, R345–R353 (2005).

    Article  CAS  PubMed  Google Scholar 

  13. Fearon, K.C., Glass, D.J. & Guttridge, D.C. Cancer cachexia: mediators, signaling, and metabolic pathways. Cell Metab. 16, 153–166 (2012).

    Article  CAS  PubMed  Google Scholar 

  14. Strassmann, G., Fong, M., Kenney, J.S. & Jacob, C.O. Evidence for the involvement of interleukin 6 in experimental cancer cachexia. J. Clin. Invest. 89, 1681–1684 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Bonetto, A. et al. STAT3 activation in skeletal muscle links muscle wasting and the acute phase response in cancer cachexia. PLoS ONE 6, e22538 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Muñoz-Cánoves, P., Scheele, C., Pedersen, B.K. & Serrano, A.L. Interleukin-6 myokine signaling in skeletal muscle: a double-edged sword? FEBS J. 280, 4131–4148 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Zhang, L. et al. Stat3 activation links a C/EBPδ to myostatin pathway to stimulate loss of muscle mass. Cell Metab. 18, 368–379 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Kiger, A.A., Jones, D.L., Schulz, C., Rogers, M.B. & Fuller, M.T. Stem cell self-renewal specified by JAK-STAT activation in response to a support cell cue. Science 294, 2542–2545 (2001).

    Article  CAS  PubMed  Google Scholar 

  19. Tulina, N. & Matunis, E. Control of stem cell self-renewal in Drosophila spermatogenesis by JAK-STAT signaling. Science 294, 2546–2549 (2001).

    Article  CAS  PubMed  Google Scholar 

  20. Oh, I.H. & Eaves, C.J. Overexpression of a dominant negative form of STAT3 selectively impairs hematopoietic stem cell activity. Oncogene 21, 4778–4787 (2002).

    Article  CAS  PubMed  Google Scholar 

  21. Doles, J., Storer, M., Cozzuto, L., Roma, G. & Keyes, W.M. Age-associated inflammation inhibits epidermal stem cell function. Genes Dev. 26, 2144–2153 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Haddad, F., Zaldivar, F., Cooper, D.M. & Adams, G.R. IL-6–induced skeletal muscle atrophy. J. Appl. Physiol. (1985) 98, 911–917 (2005).

    Article  CAS  Google Scholar 

  23. Serrano, A.L., Baeza-Raja, B., Perdiguero, E., Jardi, M. & Munoz-Canoves, P. Interleukin-6 is an essential regulator of satellite cell–mediated skeletal muscle hypertrophy. Cell Metab. 7, 33–44 (2008).

    Article  CAS  PubMed  Google Scholar 

  24. Zeidler, M.P., Bach, E.A. & Perrimon, N. The roles of the Drosophila JAK/STAT pathway. Oncogene 19, 2598–2606 (2000).

    Article  CAS  PubMed  Google Scholar 

  25. Gorissen, M., de Vrieze, E., Flik, G. & Huising, M.O. STAT genes display differential evolutionary rates that correlate with their roles in the endocrine and immune system. J. Endocrinol. 209, 175–184 (2011).

    Article  CAS  PubMed  Google Scholar 

  26. Darnell, J.E. Jr., Kerr, I.M. & Stark, G.R. Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science 264, 1415–1421 (1994).

    Article  CAS  PubMed  Google Scholar 

  27. Zhong, Z., Wen, Z. & Darnell, J.E. Jr. Stat3: a STAT family member activated by tyrosine phosphorylation in response to epidermal growth factor and interleukin-6. Science 264, 95–98 (1994).

    Article  CAS  PubMed  Google Scholar 

  28. Takeda, K. et al. Targeted disruption of the mouse Stat3 gene leads to early embryonic lethality. Proc. Natl. Acad. Sci. USA 94, 3801–3804 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Sun, L. et al. JAK1-STAT1-STAT3, a key pathway promoting proliferation and preventing premature differentiation of myoblasts. J. Cell Biol. 179, 129–138 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Wang, K., Wang, C., Xiao, F., Wang, H. & Wu, Z. JAK2/STAT2/STAT3 are required for myogenic differentiation. J. Biol. Chem. 283, 34029–34036 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Harris, J.B. & MacDonell, C.A. Phospholipase A2 activity of notexin and its role in muscle damage. Toxicon. 19, 419–430 (1981).

    Article  CAS  PubMed  Google Scholar 

  32. Megeney, L.A., Perry, R.L., LeCouter, J.E. & Rudnicki, M.A. bFGF and LIF signaling activates STAT3 in proliferating myoblasts. Dev. Genet. 19, 139–145 (1996).

    Article  CAS  PubMed  Google Scholar 

  33. Goldhamer, D.J., Faerman, A., Shani, M. & Emerson, C.P. Jr. Regulatory elements that control the lineage-specific expression of myoD. Science 256, 538–542 (1992).

    Article  CAS  PubMed  Google Scholar 

  34. Tapscott, S.J., Lassar, A.B. & Weintraub, H. A novel myoblast enhancer element mediates MyoD transcription. Mol. Cell. Biol. 12, 4994–5003 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Penn, B.H., Bergstrom, D.A., Dilworth, F.J., Bengal, E. & Tapscott, S.J.A. MyoD-generated feed-forward circuit temporally patterns gene expression during skeletal muscle differentiation. Genes Dev. 18, 2348–2353 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Asp, P. et al. Genome-wide remodeling of the epigenetic landscape during myogenic differentiation. Proc. Natl. Acad. Sci. USA 108, E149–E158 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  37. Heintzman, N.D. et al. Histone modifications at human enhancers reflect global cell-type–specific gene expression. Nature 459, 108–112 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Takeda, K. et al. Stat3 activation is responsible for IL-6–dependent T cell proliferation through preventing apoptosis: generation and characterization of T cell–specific Stat3-deficient mice. J. Immunol. 161, 4652–4660 (1998).

    CAS  PubMed  Google Scholar 

  39. 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 

  40. Palacios, D. et al. TNF/p38α/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 

  41. 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 

  42. 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 

Download references

Acknowledgements

We thank A. Cortez, J. Morales and B. Charbono for technical support. We thank the following Stanford-Burnham Medical Research Institute Core Facilities for technical support: Vivarium, Flow Cytometry, Viral Core and Cell Imaging. We thank S. Akira (Osaka University) and S. Schenk (University of California, San Diego) for providing the Stat3flox/flox mice, C. Keller (Oregon Health and Science University) and H. Makarenkova (The Scripps Research Institute) for providing the Pax7-CreER mice and H.M. Blau (Stanford University) for providing the mdx/mTRG2 mice. We thank M. Karin (University of California, San Diego) for providing the shSTAT3 construct. We thank EuroBioBank and the Telethon Network of Genetic Biobanks (GTB12001F) for providing the human biological samples. This work was supported by US National Institutes of Health (NIH) grants P30 AR061303 and R03 AR063328 and the Sanford-Burnham Center to A.S., California Institute for Regenerative Medicine (CIRM) Training grant TG2 001162 to T.A., an Italian Foreign Ministry (MAE) grant to L.L. and NIH grants R01AR056712, R01AR052779 and P30 AR061303 to P.L.P.

Author information

Authors and Affiliations

Authors

Contributions

A.S., M.T.T. and T.A. designed the experiments. T.A. performed the in vitro lentivirus and STAT3 inhibitor experiments. T.A., D.S. and M.T.T. performed experiments in the Pax7-CreER; Stat3flox/flox mice. M.T.T. performed experiments with the STAT3 inhibitor in young, aged and dystrophic mice. B.M. performed the ChIP analysis. S.G. performed the bioinformatics analysis. L.L. performed the studies on human myoblasts. All authors discussed and interpreted data. A.S., P.L.P., M.T.T., T.A. and D.S. drafted and revised the manuscript.

Corresponding author

Correspondence to Alessandra Sacco.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–8 and Supplementary Table 1 (PDF 6163 kb)

Source data

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Tierney, M., Aydogdu, T., Sala, D. et al. STAT3 signaling controls satellite cell expansion and skeletal muscle repair. Nat Med 20, 1182–1186 (2014). https://doi.org/10.1038/nm.3656

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm.3656

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing