Department of Paediatrics, University of Oxford, South Parks Road, Oxford, OX1 3QX, UK.
Central Laser Facility, Science and Technology Facilities Council, Rutherford Appleton Laboratory, Didcot, Oxfordshire, UK.
Acta Neuropathol. 2022 Jun;143(6):713-731. doi: 10.1007/s00401-022-02428-1. Epub 2022 May 6.
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.
雄激素和与雄激素相关的分子在不同组织中发挥着多种功能，主要通过与转录因子雄激素受体 (AR) 结合来实现。尽管雄激素被广泛用于治疗和滥用作为有效的合成代谢剂，但目前尚不清楚其对骨骼肌的这种作用的分子机制。成年期的肌肉质量主要通过转化生长因子 (TGF)-β 途径中的骨形态发生蛋白 (BMP) 轴通过募集母亲抗 decapentaplegic 同源物 4 (SMAD4) 蛋白来调节。在这里，我们表明，AR 在被激活后与 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转录激活活性，来协调肌肉肥大程序。我们使用脊髓和延髓肌肉萎缩症 (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展 (polyQ) 引起的，其特征是由于运动神经元变性和原发性肌肉萎缩的组合，导致进行性肌肉无力和萎缩。在这里，我们发现，长 polyQ 片段的存在会损害 AR 与 SMAD4 的协同作用，导致在去神经支配后无法在骨骼肌中启动有效的抗萎缩基因表达程序。此外，腺相关病毒，血清型 9 (AAV9)-介导的肌肉限制递送 BMP7 能够挽救 SBMA 小鼠的肌肉萎缩，支持开发能够微调 AR-SMAD4 转录协同作用的治疗方法，作为 SBMA 和其他与肌肉丧失相关的疾病的有前途的治疗靶点。
