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Inducible depletion of satellite cells in adult, sedentary mice impairs muscle regenerative capacity without affecting sarcopenia

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Abstract

A key determinant of geriatric frailty is sarcopenia, the age-associated loss of skeletal muscle mass and strength1,2. Although the etiology of sarcopenia is unknown, the correlation during aging between the loss of activity of satellite cells, which are endogenous muscle stem cells, and impaired muscle regenerative capacity has led to the hypothesis that the loss of satellite cell activity is also a cause of sarcopenia3,4. We tested this hypothesis in male sedentary mice by experimentally depleting satellite cells in young adult animals to a degree sufficient to impair regeneration throughout the rest of their lives. A detailed analysis of multiple muscles harvested at various time points during aging in different cohorts of these mice showed that the muscles were of normal size, despite low regenerative capacity, but did have increased fibrosis. These results suggest that lifelong reduction of satellite cells neither accelerated nor exacerbated sarcopenia and that satellite cells did not contribute to the maintenance of muscle size or fiber type composition during aging, but that their loss may contribute to age-related muscle fibrosis.

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Figure 1: Reduction in satellite cell content throughout the lifespan does not appear to affect mean myofiber CSA.
Figure 2: Reduction in satellite cell content leads to impaired regenerative capacity but does not appear to accelerate or exacerbate sarcopenia.
Figure 3: Age-associated fiber type–specific atrophy appears unaffected by reduction in satellite cell content.
Figure 4: Satellite cell content does not appear to affect plantaris myofiber or myonuclear number or single-fiber force production but contributes to ECM accumulation.

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Acknowledgements

The authors thank B. Lawson and K. Campbell (University of Kentucky Center for Muscle Biology) and S. Roche (University of Michigan) for technical assistance on single-fiber functional analyses; H. Bush and C. Starnes for biostatistics expertise; T. Chaillou for assistance with muscle regeneration experiments; A. Confides for assistance with grip-strength testing; and M. Ubele, R. Erfani, J. Beggs, M. Campbell, T. Kmiec, J. Werker, R. Anglin and Z. Hardyniec for image acquisition and quantification. Research was supported by the Jeane B. Kempner Postdoctoral Scholar Award and US National Institutes of Health (NIH) grant AR065337 to C.S.F.; Ellison Medical Foundation/American Federation of Aging Research (AFAR) Fellowship EPD 12102 to J.D.L.; NIH grants AG34453 to C.A.P., AG043721 to E.E.D.-V. and AR60701 to C.A.P. and J.J.M.; and the NIH National Center for Advancing Translational Sciences Award UL1TR000117. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or AFAR.

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C.S.F., J.D.L., J.J.M. and C.A.P. designed the study. C.S.F., J.D.L., J.M., T.J.K., J.R.J. and C.L.M. performed experiments and collected the data. C.S.F., J.D.L., J.M., F.L., L.Y., C.L.M. and E.E.D.-V. analyzed the data. C.S.F., J.J.M. and C.A.P. wrote the manuscript. All authors approved the final version of the manuscript.

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Correspondence to Charlotte A Peterson.

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Fry, C., Lee, J., Mula, J. et al. Inducible depletion of satellite cells in adult, sedentary mice impairs muscle regenerative capacity without affecting sarcopenia. Nat Med 21, 76–80 (2015). https://doi.org/10.1038/nm.3710

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