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.
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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.
The authors declare no competing financial interests.
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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
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