The androgen receptor polyglutamine tract sets the transcriptional balance between muscle growth and atrophy

Grafton, F.; Rohani, N.; Lim, W. F.; Ng, Y. K.; Fichera, A.; Ali, S.; Scappini, V.; Speciale, A. A.; Chalcraft, R.; Garcia-Guerra, A.; Hashimoto, Y.; Frommer, J.; Pennuto, M.; Garcia Gonzalez, E.; Zanetti-Domingues, L.; Tynan, C.; Sanders, S.; Pansini, M.; Wood, M.; Rinaldi, C.

doi:10.64898/2026.09.29.755413

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bioRxiv · 10.64898/2026.09.29.755413

The androgen receptor polyglutamine tract sets the transcriptional balance between muscle growth and atrophy

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Abstract

The androgen receptor (AR) mediates the potent anabolic effects of testosterone and other androgens on skeletal muscle, yet the transcriptional mechanisms coupling this hormonal signal to muscle growth remain unresolved. AR is a ligand-inducible transcription factor whose N-terminal transactivation domain (NTD) harbours a polymorphic polyglutamine (polyQ) tract that, when pathologically expanded, causes spinal and bulbar muscular atrophy (SBMA). To define how the NTD and its polyQ tract shape muscle transcription, we combined an engineered AR allelic series in human myogenic cells with super-resolution and single-molecule imaging, genome-wide binding and expression maps, and human population genetics. Under physiological conditions, androgen-activated AR assembles into dynamic transcriptional condensates and drives an anabolic programme in skeletal muscle through activation of the AP-1 pathway. Progressive expansion of the polyQ tract destabilises AR chromatin binding and shifts its occupancy from promoters to low-affinity distal enhancers, tracking with imaging signatures of muscle aging. In SBMA, this culminates in aberrant transactivation of ectodysplasin A2 receptor (EDA2R), a marker of senescence and inflammation, which engages non-canonical NF-{kappa}B signalling to drive muscle atrophy. Silencing Eda2r attenuated muscle wasting in SBMA mice, establishing this axis as therapeutically actionable. Together, these findings reveal a fundamental mechanism of skeletal-muscle homeostasis and open therapeutic avenues for the many conditions in which muscle atrophy is central.

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Grafton, F., Rohani, N., Lim, W. F., Ng, Y. K., Fichera, A., Ali, S., Scappini, V., Speciale, A. A., Chalcraft, R., Garcia-Guerra, A., Hashimoto, Y., Frommer, J., Pennuto, M., Garcia Gonzalez, E., Zanetti-Domingues, L., Tynan, C., Sanders, S., Pansini, M., Wood, M., Rinaldi, C.. 2026-09-30. The androgen receptor polyglutamine tract sets the transcriptional balance between muscle growth and atrophy. https://doi.org/10.64898/2026.09.29.755413

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