PDF(Pubmed)
Abstract：
The mechanism regulating cellular senescence of postmitotic muscle cells is still unknown. cGAS-STING innate immune signaling was found to mediate cellular senescence in various types of cells, including postmitotic neuron cells, which however has not been explored in postmitotic muscle cells. Here by studying the myofibers from Zmpste24-/- progeria aged mice [an established mice model for Hutchinson-Gilford progeria syndrome (HGPS)], we observed senescence-associated phenotypes in Zmpste24-/- myofibers, which is coupled with increased oxidative damage to mitochondrial DNA (mtDNA) and secretion of senescence-associated secretory phenotype (SASP) factors. Also, Zmpste24-/- myofibers feature increased release of mtDNA from damaged mitochondria, mitophagy dysfunction, and activation of cGAS-STING. Meanwhile, increased mtDNA release in Zmpste24-/- myofibers appeared to be related with increased VDAC1 oligomerization. Further, the inhibition of VDAC1 oligomerization in Zmpste24-/- myofibers with VBIT4 reduced mtDNA release, cGAS-STING activation, and the expression of SASP factors. Our results reveal a novel mechanism of innate immune activation-associated cellular senescence in postmitotic muscle cells in aged muscle, which may help identify novel sets of diagnostic markers and therapeutic targets for progeria aging and aging-associated muscle diseases.
摘要：
调节有丝分裂后肌细胞衰老的机制仍然未知。cGAS-STING先天免疫信号被发现在各种类型的细胞中介导细胞衰老，包括有丝分裂后的神经元细胞，然而，尚未在有丝分裂后的肌肉细胞中进行探索。在这里，通过研究Zmpste24-/-早衰小鼠[建立的Hutchinson-Gilford早衰综合征（HGPS）小鼠模型]的肌纤维，我们在Zmpste24-/-肌纤维中观察到衰老相关表型，与线粒体DNA（mtDNA）的氧化损伤增加和衰老相关分泌表型（SASP）因子的分泌有关。此外，Zmpste24-/-肌纤维的特征是mtDNA从受损线粒体释放增加，线粒体自噬功能障碍，和cGAS-STING的激活。同时,Zmpste24-/-肌纤维中mtDNA释放的增加似乎与VDAC1寡聚化的增加有关。Further,用VBIT4抑制Zmpste24-/-肌纤维中的VDAC1寡聚化减少了mtDNA的释放，cGAS-STING激活,和SASP因子的表达。我们的研究结果揭示了先天免疫激活相关细胞衰老的新机制，在有丝分裂后的肌肉细胞中，这可能有助于确定用于早衰症老化和老化相关肌肉疾病的新型诊断标记和治疗靶点。
