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p38 MAPK signaling underlies a cell-autonomous loss of stem cell self-renewal in skeletal muscle of aged mice

Abstract

Skeletal muscle aging results in a gradual loss of skeletal muscle mass, skeletal muscle function and regenerative capacity, which can lead to sarcopenia and increased mortality. Although the mechanisms underlying sarcopenia remain unclear, the skeletal muscle stem cell, or satellite cell, is required for muscle regeneration. Therefore, identification of signaling pathways affecting satellite cell function during aging may provide insights into therapeutic targets for combating sarcopenia. Here, we show that a cell-autonomous loss in self-renewal occurs via alterations in fibroblast growth factor receptor-1, p38α and p38β mitogen-activated protein kinase signaling in satellite cells from aged mice. We further demonstrate that pharmacological manipulation of these pathways can ameliorate age-associated self-renewal defects. Thus, our data highlight an age-associated deregulation of a satellite cell homeostatic network and reveal potential therapeutic opportunities for the treatment of progressive muscle wasting.

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Figure 1: Heterochronic transplantation of SCs from aged mice to local or systemic young environment fails to rescue age-associated phenotypes.
Figure 2: Loss of self-renewal in SCs from aged mice correlates with elevated p38 signaling.
Figure 3: Partial inhibition of p38α/β MAPK rescues aged SCs self-renewal.
Figure 4: FGFR1 signaling is altered in SCs from aged mice compared to those from young mice.
Figure 5: Constitutive FGFR1 signaling partially rescues self-renewal in SCs from aged mice.
Figure 6: Partial p38α/β MAPK inhibition rescues the engraftment of SCs from aged mice.

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Acknowledgements

We thank the Olwin lab members, especially B. Pawlikowski, M. Hall and A. Cadwallader, for revising the manuscript and helpful discussions. We thank T. Vogler, T. McClure and M. Palmer for technical assistance. N. Dalla Betta helped with mouse maintenance. C. English and the University of Colorado Boulder Molecular, Cellular and Developmental Biology Light Microscopy Core provided facilities and assistance. D.M. Spencer developed the inducible FGFR1 construct available from Addgene. This work was supported by grants from the US National Institutes of Health (AR49446 and AG040074) and The Ellison Medical Foundation to B.B.O. and from the National Institutes of Health (T32GM007135) to J.D.B.

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J.D.B. and B.B.O. conceptualized the study. J.D.B. performed and analyzed the experiments. J.K.H. assisted with transplantation experiments. K.K.T. designed and performed the collection of microarray data. J.D.D. performed the microarray analysis. T.A.C. assisted with image scoring. J.D.B., B.B.O. and J.D.D. wrote, discussed and edited the manuscript. B.B.O. supervised the project.

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Correspondence to Bradley B Olwin.

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Supplementary Figures 1–5, Supplementary Methods and Supplementary Table 1 (PDF 2038 kb)

Phospho-p38αβ MAPK is asymmetrically localized across satellite cell.

Three-dimensional rendering of a myofiber-associated satellite cell at 24 h after isolation. DAPI (blue), syndecan-4 (red) and phospho-p38 (green). Syndecan-4 cell is a myonucleus. (AVI 2682 kb)

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Bernet, J., Doles, J., Hall, J. et al. p38 MAPK signaling underlies a cell-autonomous loss of stem cell self-renewal in skeletal muscle of aged mice. Nat Med 20, 265–271 (2014). https://doi.org/10.1038/nm.3465

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