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.
Highlights
Cellular senescence, a form of persistent cell cycle arrest, was initially considered to reflect the finite proliferative capacity of cultured cells [1]; senescent cells were subsequently discovered to be induced by various types of stress, including oxidative stress [2]
Muscle frequently exhibits adipose- and fibrous-tissue infiltration [14], and this impairs skeletal muscle function: whereas intramuscular adipose tissue (IMAT) causes poor physical performance [15], fibrous tissue reduces motile and contractile functions [16]. Both IMAT and fibrous tissue have been widely shown to be derived from mesenchymal progenitor cells (MPCs), which reside in the interstitial space in skeletal muscle [17, 18] and whose fibro/adipogenic potential is regulated by secreted growth factors: TGFβ upregulates the expression of the fibroblast markers collagen type 1 (Col1a1), connective-tissue growth factor (CTGF), and α-actin-2 (Acta2) [19], and basic fibroblast growth factor promotes the adipogenic programme of skeletal muscle adipogenic cells, as we reported previously [20]
Histological analysis of tibialis anterior (TA) muscle sections revealed that several cells present only in the old rat skeletal muscle were positive for senescence-associated β-galactosidase (SA-βGal) staining, and the cells appeared to exist in the interstitial space around muscle fibres (Fig. 1B, C)
Summary
A form of persistent cell cycle arrest, was initially considered to reflect the finite proliferative capacity of cultured cells [1]; 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”. Such stress-induced premature senescent cells have been shown to be present in vivo, in aged animals, including humans [3]. Senescent cells frequently exhibit high lysosomal activity of β-galactosidase, called senescence-associated β-galactosidase (SA-βGal) www.aging‐us.com 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 ageassociated diseases [5]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
