Senescence of myogenic progenitors impedes skeletal muscle regeneration. Here, we show that overexpression of the transcription factor NANOG in senescent myoblasts can overcome the effects of cellular senescence and confer a youthful phenotype to senescent cells. NANOG ameliorated primary hallmarks of cellular senescence including genomic instability, loss of proteostasis, and mitochondrial dysfunction. The rejuvenating effects of NANOG included restoration of DNA damage response via up-regulation of DNA repair proteins, recovery of heterochromatin marks via up-regulation of histones, and reactivation of autophagy and mitochondrial energetics via up-regulation of AMP-activated protein kinase (AMPK). Expression of NANOG in the skeletal muscle of a mouse model of premature aging restored the number of myogenic progenitors and induced formation of eMyHC⁺ myofibers. This work demonstrates the feasibility of reversing the effects of cellular senescence in vitro and in vivo, with no need for reprogramming to the pluripotent state.

中文翻译：

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改善体外和体内骨骼肌肌源性祖细胞的细胞衰老特征


肌源性祖细胞的衰老阻碍骨骼肌再生。在这里，我们证明转录因子 NANOG 在衰老成肌细胞中的过度表达可以克服细胞衰老的影响并赋予衰老细胞年轻的表型。 NANOG 改善了细胞衰老的主要标志，包括基因组不稳定、蛋白质稳态丧失和线粒体功能障碍。 NANOG 的返老还童作用包括通过上调 DNA 修复蛋白恢复 DNA 损伤反应、通过上调组蛋白恢复异染色质标记，以及通过上调 AMP 激活蛋白激酶 (AMPK) 重新激活自噬和线粒体能量学。 ）。 NANOG 在早衰小鼠模型骨骼肌中的表达恢复了肌源性祖细胞的数量并诱导了 eMyHC ⁺肌纤维的形成。这项工作证明了在体外和体内逆转细胞衰老影响的可行性，而无需重新编程为多能状态。