TY - JOUR

T1 - Rejuvenation of the muscle stem cell population restores strength to injured aged muscles

AU - Cosgrove, Benjamin D

AU - Gilbert, Penney M

AU - Porpiglia, Ermelinda

AU - Mourkioti, Foteini

AU - Lee, Steven P

AU - Corbel, Stephane Y

AU - Llewellyn, Michael E

AU - Delp, Scott L

AU - Blau, Helen M

PY - 2014/3

Y1 - 2014/3

N2 - 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.

AB - 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.

KW - Aging

KW - Animals

KW - Cell Proliferation

KW - Cell Transplantation

KW - Cellular Senescence

KW - Cyclin-Dependent Kinase Inhibitor p16/metabolism

KW - Cyclin-Dependent Kinase Inhibitor p21/metabolism

KW - Female

KW - Green Fluorescent Proteins/metabolism

KW - Hydrogels/chemistry

KW - Male

KW - Mice

KW - Mice, Inbred C57BL

KW - Mice, Inbred NOD

KW - Mice, SCID

KW - Mice, Transgenic

KW - Mitogen-Activated Protein Kinase 11/metabolism

KW - Mitogen-Activated Protein Kinase 14/metabolism

KW - Muscle Fibers, Skeletal/metabolism

KW - Muscle Strength

KW - Muscles/cytology

KW - Phenotype

KW - Phosphoproteins/metabolism

KW - Regeneration

KW - Rejuvenation

KW - Stem Cell Transplantation

KW - Stem Cells/cytology

KW - Time Factors

U2 - 10.1038/nm.3464

DO - 10.1038/nm.3464

M3 - Journal article

C2 - 24531378

VL - 20

SP - 255

EP - 264

JO - Nature Medicine

JF - Nature Medicine

SN - 1078-8956

IS - 3

ER -