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

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-kappa B activation. We find that prolonged NF-kappa B 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-kappa B 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.

Automated summary

Repeated cycles of damage and repair in muscle disorders like DMD can lead to inefficiency in muscle stem cell response. The early telomere shortening in diseased MuSCs is associated with aberrant NF-kappa B activation, leading to severe skeletal muscle defects. NF-kappa B plays a role in regulating stem-cell-specific telomere length and could be a common mechanism in diseases characterized by chronic inflammation.