Persistent NF-κB activation in muscle stem cells induces proliferation-independent telomere shortening.
Persistent NF-κB activation in muscle stem cells induces proliferation-independent telomere shortening.
复制标题
DOI：
10.1016/j.celrep.2021.109098
复制
发表时间：
2021-05-11
期刊：
影响因子：
8.8
通讯作者：
Mourkioti F
中科院分区：
文献类型：
--
作者：
Tichy ED;Ma N;Sidibe D;Loro E;Kocan J;Chen DZ;Khurana TS;Hasty P;Mourkioti F
在包括Duchenne肌营养不良(DMD)在内的许多肌肉疾病的反复损伤和修复周期中，肌肉干细胞(MUSC)池对损伤的反应和修复效率降低。这种干细胞功能障碍的潜在机制尚不完全清楚。在这里，我们证明，在小鼠和年轻的DMD患者中，患病的MUSCs明显的早期端粒缩短与异常的NF-κB激活有关。我们发现，在慢性损伤中，MUSCs中NF-κB的长时间激活会导致端粒缩短和Ku80调节失调，并导致严重的骨骼肌缺陷。我们的研究提供了证据表明，NF-κB在调节干细胞特异性端粒长度方面发挥了作用，而不是细胞复制，并且可能是一种一致的机制，适用于其他组织和/或以系统性慢性炎症为特征的疾病。Tichy等人。揭示核因子-κB信号在肌肉干细胞(MUSCs)慢性损伤后调节端粒长度中的作用。NF-κB的持续激活会导致端粒缩短、Ku80失调和肌肉缺陷。这一发现将杜氏肌营养不良症中干细胞功能障碍与依赖于核因子-κB的端粒缩短联系在一起。
During the repeated cycles of damage and repair in many muscle disorders, including Duchenne muscular dystrophy (DMD), the muscle stem cell (MuSC) pool becomes less efficient at responding to and repairing damage. The underlying mechanism of such stem cell dysfunction is not fully known. Here, we demonstrate that the distinct early telomere shortening of diseased MuSCs in both mice and young DMD patients is associated with aberrant NF-κB activation. We find that prolonged NF-κB activation in MuSCs in chronic injuries leads to shortened telomeres and Ku80 dysregulation and results in severe skeletal muscle defects. Our studies provide evidence of a role for NF-κB in regulating stem-cell-specific telomere length, independently of cell replication, and could be a congruent mechanism that is applicable to additional tissues and/or diseases characterized by systemic chronic inflammation. Tichy et al. reveal a role for NF-κB signaling in regulating telomere length in muscle stem cells (MuSCs) after chronic injuries. Persistent activation of NF-κB leads to shortened telomeres, Ku80 dysregulation, and muscle defects. The findings link stem cell dysfunction and NF-κB-dependent telomere shortening in Duchenne muscular dystrophy.
登录
查看更多内容
影响因子：
50.3
作者：
Calado DP;Zhang B;Srinivasan L;Sasaki Y;Seagal J;Unitt C;Rodig S;Kutok J;Tarakhovsky A;Schmidt-Supprian M;Rajewsky K
通讯作者：
Rajewsky K
影响因子：
8
作者：
Hammers, David W.;Sleeper, Margaret M.;Sweeney, H. Lee
通讯作者：
Sweeney, H. Lee
影响因子：
1.2
作者：
Boldrin, Luisa;Zammit, Peter S.;Morgan, Jennifer E.
通讯作者：
Morgan, Jennifer E.
影响因子：
4.8
作者：
Chai, WH;Ford, LP;Shay, JW
通讯作者：
Shay, JW
影响因子：
10.5
作者：
Hsu, HL;Gilley, D;Chen, DJ
通讯作者：
Chen, DJ