Sugihara Hidetoshi, Teramoto Naomi, Yamanouchi Keitaro, Matsuwaki Takashi, Nishihara Masugi
Department of Veterinary Physiology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo 113-8657, Japan.
Aging (Albany NY). 2018 Apr 25;10(4):747-763. doi: 10.18632/aging.101425.
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. HO 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.
肌肉减少症是与年龄相关的骨骼肌质量和功能丧失。骨骼肌包含多种祖细胞，包括间充质祖细胞（MPCs），这些细胞通常支持成肌细胞功能，但在分化为纤维/脂肪组织后会导致骨骼肌功能下降。细胞衰老一种由细胞应激（包括氧化应激）引起的持续性细胞周期停滞形式，并且伴随着衰老相关分泌表型（SASP）的获得。在这里，我们发现γH2AX衰老细胞出现在骨骼肌的间质中，其位置与MPCs相对应。HO介导我们实验室先前建立的大鼠MPC克隆2G11细胞中的氧化应激，成功诱导了衰老，这通过p21和SASP因子（包括IL-6）的上调得以证明。衰老的2G11细胞失去了其成纤维/脂肪生成潜能，但有趣的是，将成肌细胞与衰老的2G11细胞共培养会抑制肌管形成，这与肌生成细胞融合中涉及的肌肉特异性蛋白myomaker的下调相一致；然而，强制表达myomaker并不能挽救这种抑制作用。这些结果表明，老年大鼠骨骼肌中的衰老MPCs失去了其成纤维/脂肪生成潜能，但与未分化的祖细胞完全不同，因为衰老的MPCs会抑制成肌细胞融合，从而可能加速肌肉减少症。
