title: Rejuvenation of the muscle stem cell population restores strength to injured aged muscles.
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.
authors: 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.
authors: Benjamin D
authors: BD
authors: Cosgrove
authors: 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. [2] Institute of Biomaterials and Biomedical Engineering and Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario, Canada.
authors: Penney M
authors: PM
authors: Gilbert
authors: 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.
authors: Ermelinda
authors: E
authors: Porpiglia
authors: 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.
authors: Foteini
authors: F
authors: Mourkioti
authors: 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.
authors: Steven P
authors: SP
authors: Lee
authors: 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.
authors: Stephane Y
authors: SY
authors: Corbel
authors: Department of Bioengineering, Stanford University School of Medicine, Stanford, California, USA.
authors: Michael E
authors: ME
authors: Llewellyn
authors: 1] Department of Bioengineering, Stanford University School of Medicine, Stanford, California, USA. [2] Department of Mechanical Engineering, Stanford University School of Medicine, Stanford, California, USA.
authors: Scott L
authors: SL
authors: Delp
authors: 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.
authors: Helen M
authors: HM
authors: Blau
mesh_terms: D000375:Aging; D000818:Animals; D049109:Cell Proliferation; D017690:Cell Transplantation; D016922:Cellular Senescence; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D005260:Female; D049452:Green Fluorescent Proteins / Q000378:metabolism; D020100:Hydrogels / Q000737:chemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D048290:Mitogen-Activated Protein Kinase 11 / Q000378:metabolism; D048308:Mitogen-Activated Protein Kinase 14 / Q000378:metabolism; D018485:Muscle Fibers, Skeletal / Q000378:metabolism; D053580:Muscle Strength; D009132:Muscles / Q000166:cytology*; D010641:Phenotype; D010750:Phosphoproteins / Q000378:metabolism; D012038:Regeneration; D012060:Rejuvenation; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000166:cytology*; D013997:Time Factors
chemical_list: C493957:Cdkn1a protein, mouse; C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; D020100:Hydrogels; D010750:Phosphoproteins; D049452:Green Fluorescent Proteins; D048290:Mitogen-Activated Protein Kinase 11; D048308:Mitogen-Activated Protein Kinase 14