Persistent NF-κB activation in muscle stem cells induces proliferation-independent telomere shortening

• DOI: 10.1016/j.celrep.2021.109098
• Publication Date: 2021-05-11T15:53:33Z
• Authors: Elisia D. Tichy; Nuoying Ma; David Sidibe; Emanuele Loro; Jacob Kocan; Delia Z. Chen; Tejvir S. Khurana; Paul Hasty; Foteini Mourkioti
• Keywords: 0301 basic medicine; Disease Models, Animal; Mice; 03 medical and health sciences; Stem Cells; NF-kappa B; Animals; Humans; Article; Telomere Shortening; Cell Proliferation

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.