Cellular senescence mediates facioscapulohumeral muscular dystrophy

Facioscapulohumeral muscular dystrophy (FSHD) is driven by aberrant expression of the early embryonic transcription factor Double Homeobox 4 (DUX4), yet the mechanisms linking low, sporadic DUX4 activity to progressive muscle degeneration remain unclear. Here, we identify cellular senescence as a central and early mechanism in FSHD pathogenesis. Analysis of patient muscle transcriptomes revealed strong enrichment of senescence and senescence-associated secretory phenotype (SASP) programs that correlated with DUX4 activity, clinical severity, and histopathological changes. Notably, these signatures were detectable even in STIR-negative muscles, defining a prodystrophic state characterized by early molecular alterations preceding overt MRI-detectable inflammation and highlighting their potential utility as early biomarkers of disease activity. Using an FSHD mouse model, we show that DUX4-induced muscle injury rapidly triggers senescence, which then progressively expands. Fibroadipogenic progenitors and macrophages emerged as the principal senescent populations and key sources of pro-inflammatory and profibrotic SASP signals. Importantly, senescence was therapeutically modifiable. Treatment with the nucleoside reverse transcriptase inhibitor lamivudine (3TC), which inhibits LINE-1 reverse transcriptase activity, significantly reduced senescence, inflammation, and fibrosis while promoting muscle regeneration. These findings identify cellular senescence as a tractable driver of FSHD and warrant senotherapeutic strategies, particularly lamivudine, for clinical intervention in FSHD.