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

By B. Cosgrove, P. Gilbert, E. Porpiglia, F. Mourkioti, Steven P. Lee, S. Corbel, Michael E. Llewellyn, Scott L. Delp, Helen M. Blau. Nature Medicine, 2014

602 citations recorded by the source corpus.

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.

Subfields: Aging, Molecular Biology, Physiology

View Paper: https://www.semanticscholar.org/paper/0ea4a28abfa81adefa98edee35214398f8187813

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Citations in the corpus

In Vivo Amelioration of Age-Associated Hallmarks by Partial Reprogramming (2016, positive): “The age-associated loss of muscle mass during aging results from a decline in the regenerative capacity of muscle stem cells, also known as satellite cells (Chakkalakal et al., 2012; Cosgrove et al., 2014).”
Senescence and aging: Causes, consequences, and therapeutic avenues (2018, background): “Additionally, inhibition of p38 or p16INK4a bypasses MuSC senescence and strengthens muscle in geriatric mice (Cosgrove et al., 2014; Sousa-Victor et al., 2014).”
Satellite Cells and Skeletal Muscle Regeneration (2015, positive): “Increased p38 α / β signaling in aged satellite cells has also been shown to stimulate the expression of senescence markers (74).”