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Inhibition of JAK-STAT signaling stimulates adult satellite cell function

A Corrigendum to this article was published on 07 April 2015

A Corrigendum to this article was published on 08 October 2014

This article has been updated

Abstract

Diminished regenerative capacity of skeletal muscle occurs during adulthood. We identified a reduction in the intrinsic capacity of mouse adult satellite cells to contribute to muscle regeneration and repopulation of the niche. Gene expression analysis identified higher expression of JAK-STAT signaling targets in 18-month-old relative to 3-week-old mice. Knockdown of Jak2 or Stat3 significantly stimulated symmetric satellite stem cell divisions on cultured myofibers. Genetic knockdown of Jak2 or Stat3 expression in prospectively isolated satellite cells markedly enhanced their ability to repopulate the satellite cell niche after transplantation into regenerating tibialis anterior muscle. Pharmacological inhibition of Jak2 and Stat3 activity similarly stimulated symmetric expansion of satellite cells in vitro and their engraftment in vivo. Intramuscular injection of these drugs resulted in a marked enhancement of muscle repair and force generation after cardiotoxin injury. Together these results reveal age-related intrinsic properties that functionally distinguish satellite cells and suggest a promising therapeutic avenue for the treatment of muscle-wasting diseases.

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Figure 1: Increasing age negatively affects the engraftment capacity of satellite cells.
Figure 2: The transcriptional profile of adult satellite cells is enriched for JAK-STAT signaling pathway members and interactors.
Figure 3: Inhibition of JAK-STAT signaling rescues the proliferation defect of satellite cells from the muscle of older adult mice.
Figure 4: Knockdown of JAK-STAT pathway members ameliorates the engraftment potential of adult satellite cells.
Figure 5: Administration of small-molecule JAK-STAT inhibitors ex vivo before transplantation into young adult mice enhances engraftment.
Figure 6: Direct injection of JAK-STAT inhibitors in vivo improves muscle regeneration, increases satellite cell number and functionally improves skeletal muscle.

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  • 22 September 2014

     In the version of this article initially published online, the third sentence of the Abstract read “Gene expression analysis identified higher expression of JAK-STAT signaling targets in 3-week-old relative to 18-month-old mice,” when it should have read “Gene expression analysis identified higher expression of JAK-STAT signaling targets in 18-month-old relative to 3-week-old mice.” The error has been corrected for the print, PDF and HTML versions of this article.

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Acknowledgements

We thank P. Oleynik for conducting cell sorting and providing guidance regarding FACS isolation and analysis. We thank J. Ritchie for mouse husbandry, A. Grayston for his help with myofibers counts and G. Palidwor for RMA normalization of microarray data sets and constructive discussions. We thank V. Soleimani for constructive discussions and access to unpublished microarray data. We thank M. Kyba, University of Minnesota, for the Pax7-ZsGreen mice. F.D.P. was supported by the Canadian Stem Cell Network and a Doctoral Research Award from the Canadian Institutes of Health Research. J.v.M. was supported by a grant from the German Research Foundation (MA-3975/2-1). C.F.B. was supported by the Swiss National Science Foundation. M.A.R. holds the Canada Research Chair in Molecular Genetics. These studies were carried out with support of grants to M.A.R. from the US National Institutes of Health (R01AR044031), the Canadian Institutes for Health Research (MOP-81288), the Stem Cell Network and the Ontario Ministry of Economic Development and Innovation.

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F.D.P. designed and carried out experiments, analyzed results and wrote the manuscript. J.v.M. designed and conducted experiments and analyzed results. C.F.B., N.A.D., H.Y. and N.C.C. conducted experiments and analyzed and interpreted data. D.H.W. conducted experiments. J.F. provided expertise in physiological analysis. M.A.R. designed experiments, analyzed results, wrote the manuscript and provided financial support.

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Correspondence to Michael A Rudnicki.

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Price, F., von Maltzahn, J., Bentzinger, C. et al. Inhibition of JAK-STAT signaling stimulates adult satellite cell function. Nat Med 20, 1174–1181 (2014). https://doi.org/10.1038/nm.3655

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