Article | Published:

Rejuvenation of the muscle stem cell population restores strength to injured aged muscles

Nature Medicine volume 20, pages 255264 (2014) | Download Citation

Abstract

The elderly often suffer from progressive muscle weakness and regenerative failure. We demonstrate that muscle regeneration is impaired with aging owing in part to a cell-autonomous functional decline in skeletal muscle stem cells (MuSCs). Two-thirds of MuSCs from aged mice are intrinsically defective relative to MuSCs from young mice, with reduced capacity to repair myofibers and repopulate the stem cell reservoir in vivo following transplantation. This deficiency is correlated with a higher incidence of cells that express senescence markers and is due to elevated activity of the p38α and p38β mitogen-activated kinase pathway. We show that these limitations cannot be overcome by transplantation into the microenvironment of young recipient muscles. In contrast, subjecting the MuSC population from aged mice to transient inhibition of p38α and p38β in conjunction with culture on soft hydrogel substrates rapidly expands the residual functional MuSC population from aged mice, rejuvenating its potential for regeneration and serial transplantation as well as strengthening of damaged muscles of aged mice. These findings reveal a synergy between biophysical and biochemical cues that provides a paradigm for a localized autologous muscle stem cell therapy for the elderly.

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Acknowledgements

We thank K. Koleckar, P. Kraft, N. Nguyen, A. Thayer, C. Marceau, K. Magnusson and A. Ho for technical assistance; K. Havenstrite and R. Haynes for polymer synthesis; and the Stanford Center for Innovation in In-Vivo Imaging (SCI3), the Stanford Shared FACS Facility (SSFF) and IBM Almaden for technical support. This work was funded by US National Institutes of Health (NIH) training grant R25CA118681 and grant K99AG042491 (B.D.C.); NIH training grant T32CA009151 and grant K99AR061465 and California Institute for Regenerative Medicine training grant TG2-01159 (P.M.G.); and NIH grants U01HL100397, U01HL099997, R01AG020961, R01HL096113 and R01AG009521, an IBM Faculty Award, California Institute for Regenerative Medicine grants RT1-01001 and TR3-05501 and the Baxter Foundation (H.M.B.).

Author information

Affiliations

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

    • Benjamin D Cosgrove
    • , Penney M Gilbert
    • , Ermelinda Porpiglia
    • , Foteini Mourkioti
    • , Steven P Lee
    • , Stephane Y Corbel
    •  & Helen M Blau
  2. Institute of Biomaterials and Biomedical Engineering and Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario, Canada.

    • Penney M Gilbert
  3. Department of Bioengineering, Stanford University School of Medicine, Stanford, California, USA.

    • Michael E Llewellyn
    •  & Scott L Delp
  4. Department of Mechanical Engineering, Stanford University School of Medicine, Stanford, California, USA.

    • Scott L Delp

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Contributions

B.D.C., P.M.G. and E.P. designed and performed experiments, analyzed data and wrote the manuscript. F.M., S.P.L., S.Y.C. and M.E.L. developed methods, performed experiments and analyzed data. S.L.D. developed methods and wrote the manuscript. H.M.B. designed experiments, analyzed data and wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Penney M Gilbert or Helen M Blau.

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DOI

https://doi.org/10.1038/nm.3464

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