AR cooperates with SMAD4 to maintain skeletal muscle homeostasis.
AR cooperates with SMAD4 to maintain skeletal muscle homeostasis.
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DOI：
10.1007/s00401-022-02428-1
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发表时间：
2022-06
影响因子：
12.7
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中科院分区：
文献类型：
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雄激素和雄激素相关分子主要通过与转录因子雄激素受体（AR）结合，在不同组织中发挥多种功能。尽管广泛的治疗用途和滥用雄激素作为有效的合成代谢剂，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由转化生长因子（TGF）-β途径的骨形态发生蛋白（BMP）轴通过招募母亲抗十肢瘫痪同源物4（SMAD 4）蛋白来调节。在这里，我们表明，激活后，AR形成一个转录复合物与SMAD 4协调肌肉肥大程序通过调节SMAD 4染色质结合动力学和增强其反式激活活性。我们使用脊髓延髓肌萎缩症（SBMA）作为研究模型来挑战这种作用机制。这种成人发作的神经肌肉疾病是由AR中的多聚谷氨酰胺扩增（polyQ）引起的，其特征在于继发于下运动神经元变性和原发性肌肉萎缩的组合的进行性肌无力和萎缩。在这里，我们发现，延长polyQ束的存在损害了AR与SMAD 4的协同性，导致无法在骨骼肌中响应去神经支配而建立有效的抗萎缩基因表达程序。此外，腺相关病毒血清型9（AAV 9）介导的BMP 7的肌肉限制性递送能够挽救SBMA小鼠中的肌肉萎缩，支持能够微调AR-SMAD 4转录协同性的治疗的开发，作为SBMA和与肌肉损失相关的其他病症的有希望的靶标。在线版本包含补充材料，可通过10.1007/s 00401 -022-02428-1获得。
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. The online version contains supplementary material available at 10.1007/s00401-022-02428-1.
DOI：
10.1007/978-1-61779-477-3_12
发表时间：
2012
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
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作者：
Mazza D;Stasevich TJ;Karpova TS;McNally JG
通讯作者：
McNally JG