Androgens and androgen-related molecules exert a plethora of functions across different tissues, mainly through binding to the transcription factor androgen receptor (AR). Despite widespread therapeutic use and misuse of androgens as potent anabolic agents, the molecular mechanisms of this effect on skeletal muscle are currently unknown. Muscle mass in adulthood is mainly regulated by the bone morphogenetic protein (BMP) axis of the transforming growth factor (TGF)-β pathway via recruitment of mothers against decapentaplegic homolog 4 (SMAD4) protein. Here we show that, upon activation, AR forms a transcriptional complex with SMAD4 to orchestrate a muscle hypertrophy programme by modulating SMAD4 chromatin binding dynamics and enhancing its transactivation activity. We challenged this mechanism of action using spinal and bulbar muscular atrophy (SBMA) as a model of study. This adult-onset neuromuscular disease is caused by a polyglutamine expansion (polyQ) in AR and is characterized by progressive muscle weakness and atrophy secondary to a combination of lower motor neuron degeneration and primary muscle atrophy. Here we found that the presence of an elongated polyQ tract impairs AR cooperativity with SMAD4, leading to an inability to mount an effective anti-atrophy gene expression programme in skeletal muscle in response to denervation. Furthermore, adeno-associated virus, serotype 9 (AAV9)-mediated muscle-restricted delivery of BMP7 is able to rescue the muscle atrophy in SBMA mice, supporting the development of treatments able to fine-tune AR-SMAD4 transcriptional cooperativity as a promising target for SBMA and other conditions associated with muscle loss.

雄激素和雄激素相关分子在不同组织中发挥多种功能，主要是通过与转录因子雄激素受体 (AR) 结合。尽管雄激素作为有效的合成代谢剂广泛用于治疗和滥用，但这种作用对骨骼肌的分子机制目前尚不清楚。成年期的肌肉质量主要受转化生长因子 (TGF)-β 通路的骨形态发生蛋白 (BMP) 轴的调节，通过募集母亲对抗去瘫痪同源物 4 (SMAD4) 蛋白。在这里，我们表明，激活后，AR 与 SMAD4 形成转录复合物，通过调节 SMAD4 染色质结合动力学并增强其反式激活活性来协调肌肉肥大程序。我们使用脊髓和延髓肌萎缩症 (SBMA) 作为研究模型来挑战这种作用机制。这种成人发病的神经肌肉疾病是由 AR 中的多聚谷氨酰胺扩张 (polyQ) 引起的，其特征是进行性肌肉无力和继发于下运动神经元退化和原发性肌肉萎缩的组合的萎缩。在这里，我们发现细长的 polyQ 束的存在会损害 AR 与 SMAD4 的协同性，导致无法在骨骼肌中启动有效的抗萎缩基因表达程序以响应去神经支配。此外，腺相关病毒血清型 9 (AAV9) 介导的 BMP7 肌肉限制递送能够挽救 SBMA 小鼠的肌肉萎缩，