Cellular senescence mediates facioscapulohumeral muscular dystrophy

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Abstract

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.

Authors

Usuk Jung, Erdong Wei, Ana Mitanoska, Philipp Heher, Kenric Chen, Haseeb Ahsan, Xu Zhang, Giorgio Tasca, Paul D. Robbins, Nathan K. LeBrasseur, Michael Kyba, Darko Bosnakovski