Research Paper Volume 10, Issue 4 pp 747—763
Oxidative stress-mediated senescence in mesenchymal progenitor cells causes the loss of their fibro/adipogenic potential and abrogates myoblast fusion
- 1 Department of Veterinary Physiology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo 113-8657, Japan
Received: February 28, 2018 Accepted: April 20, 2018 Published: April 25, 2018https://doi.org/10.18632/aging.101425
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Copyright: Sugihara et al. This is an open‐access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Sarcopenia is the age-related loss of skeletal muscle mass and function. Skeletal muscle comprises diverse progenitor cells, including mesenchymal progenitor cells (MPCs), which normally support myogenic cell function but cause a decline in skeletal muscle function after differentiating into fibrous/adipose tissue. Cellular senescence is a form of persistent cell cycle arrest caused by cellular stress, including oxidative stress, and is accompanied by the acquisition of senescence-associated secretory phenotype (SASP). Here, we found γH2AX+ senescent cells appeared in the interstitium in skeletal muscle, corresponding in position to that of MPCs. H2O2 mediated oxidative stress in 2G11 cells, a rat MPC clone previously established in our laboratory, successfully induced senescence, as shown by the upregulation of p21 and SASP factors, including IL-6. The senescent 2G11 cells lost their fibro/adipogenic potential, but, intriguingly, coculture of myoblasts with senescent 2G11 cells abrogated the myotube formation, which coincided with the downregulation of myomaker, a muscle-specific protein involved in myogenic cell fusion; however, forced expression of myomaker could not rescue this abrogation. These results suggest that senescent MPCs in aged rat skeletal muscle lose their fibro/adipogenic potential, but differ completely from undifferentiated progenitor cells in that senescent MPCs suppress myoblast fusion and thereby potentially accelerate sarcopenia.