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

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

DOI

  • Benjamin D Cosgrove, Stanford University
  • ,
  • Penney M Gilbert, University of Toronto
  • ,
  • Ermelinda Porpiglia
  • Foteini Mourkioti, Stanford University
  • ,
  • Steven P Lee, Stanford University
  • ,
  • Stephane Y Corbel, Stanford University
  • ,
  • Michael E Llewellyn, Stanford University
  • ,
  • Scott L Delp, Stanford University
  • ,
  • Helen M Blau, Stanford University
  • Department of Medical Microbiology and Immunology

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.

Original languageEnglish
JournalNature Medicine
Volume20
Issue3
Pages (from-to)255-64
Number of pages10
ISSN1078-8956
DOIs
Publication statusPublished - Mar 2014

    Research areas

  • Aging, Animals, Cell Proliferation, Cell Transplantation, Cellular Senescence, Cyclin-Dependent Kinase Inhibitor p16/metabolism, Cyclin-Dependent Kinase Inhibitor p21/metabolism, Female, Green Fluorescent Proteins/metabolism, Hydrogels/chemistry, Male, Mice, Mice, Inbred C57BL, Mice, Inbred NOD, Mice, SCID, Mice, Transgenic, Mitogen-Activated Protein Kinase 11/metabolism, Mitogen-Activated Protein Kinase 14/metabolism, Muscle Fibers, Skeletal/metabolism, Muscle Strength, Muscles/cytology, Phenotype, Phosphoproteins/metabolism, Regeneration, Rejuvenation, Stem Cell Transplantation, Stem Cells/cytology, Time Factors

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