Research Article: Oxidative stress-mediated senescence in mesenchymal progenitor cells causes the loss of their fibro/adipogenic potential and abrogates myoblast fusion

Date Published: April 25, 2018

Publisher: Impact Journals

Author(s): Hidetoshi Sugihara, Naomi Teramoto, Keitaro Yamanouchi, Takashi Matsuwaki, Masugi Nishihara.

http://doi.org/10.18632/aging.101425

Abstract

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.

Partial Text

Cellular senescence, a form of persistent cell cycle arrest, was initially considered to reflect the finite proliferative capacity of cultured cells [1]; however, senescent cells were subsequently discovered to be induced by various types of stress, including oxidative stress [2]. These senescent cells are called as “premature senescent cells” in distinction from “replicative senescent cells”. Recently, such stress-induced premature senescent cells have been shown to also be present in vivo, particularly in aged animals, including humans [3]. Ageing stimulates the production of high levels of reactive oxygen species [4], which is assumed to be one cause of senescence. Senescent cells differ from other nonproliferating cells in terms of their morphological changes and the expression of several markers, including the expression of antiproliferative molecules such as p16INK4a, p19ARF (p14ARF in humans), and p21 [5]; p21 expression is regulated by p53 tumour-suppressor protein, which is governed by the expression of p19ARF, and p16 maintains the hypophosphorylated state of retinoblastoma protein (pRB) and eventually arrests the cell cycle. Senescent cells frequently exhibit high lysosomal activity of β-galactosidase, called senescence-associated β-galactosidase (SA-βGal) activity, and secrete various cytokines, including interleukin-6 (IL-6), transforming growth factor (TGF) β, and C-C motif chemokine ligand 2 (CCL2) [5], and this senescence-associated secretory phenotype (SASP) is recognised to be involved in the progression of age-associated diseases [5].

In this study, we demonstrated that senescent cells were present in the interstitial space in aged skeletal muscle, in a position corresponding to that of MPCs. Senescent MPC-clone 2G11 cells showed a loss of their fibro/adipogenic potential, but strongly inhibited myotube formation by abrogating the fusogenic potential of skeletal muscle progenitor cells through SASP.

 

Source:

http://doi.org/10.18632/aging.101425

 

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