A muscle growth-promoting treatment based on the attenuation of activin/myostatin signalling results in long-term testicular abnormalities.
A muscle growth-promoting treatment based on the attenuation of activin/myostatin signalling results in long-term testicular abnormalities.
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DOI：
10.1242/dmm.047555
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发表时间：
2021-02-19
影响因子：
4.3
通讯作者：
Patel K
中科院分区：
文献类型：
--
作者：
Vaughan D;Mitchell R;Kretz O;Chambers D;Lalowski M;Amthor H;Ritvos O;Pasternack A;Matsakas A;Vaiyapuri S;Huber TB;Denecke B;Mukherjee A;Widera D;Patel K
激活素/肌肉抑制素信号通路通过抑制蛋白质合成和促进蛋白质和细胞器的周转来诱导成年哺乳动物骨骼肌萎缩。许多策略已经被成功地开发出来，以减弱这些分子的信号特性，从而导致肌肉生长增强。然而，这些分子，特别是激活素，在哺乳动物体内许多器官的组织动态平衡中发挥着重要作用。我们最近的研究表明，虽然激活素/肌肉抑制素的减弱会导致肌肉生长旺盛，但它也会对睾丸产生不利影响。在这里，我们的目标是发现短期暴露于睾丸中促进肌肉生长的分子的长期后果。我们证明，由可溶性激活素IIB配体陷阱(SActRIIB)促进的肌肉肥大是一种短暂的现象。与之形成鲜明对比的是，使用sActRIIB的短期治疗会立即对睾丸产生影响，这种影响在干预后仍会持续。基因阵列分析发现，随着时间的推移，睾丸中异常基因表达的扩大，是由短暂接触肌肉生长促进分子启动的。对睾丸的影响导致器官尺寸减小，并对精子产生数量和质量上的影响。最后，我们使用了药物再利用策略来利用基因表达数据来确定一种化合物-N6-甲基腺苷-可能保护睾丸免受肌肉生长促进机制的影响。这项工作表明了旨在通过减弱激活素/肌肉生长抑制素信号来促进肌肉生长的策略的潜在长期有害影响。此外，我们已经确定了一种分子，在未来可以用来克服sActRIIB治疗对睾丸的有害影响。编者按：小鼠睾丸短暂暴露于一种促进肌肉生长的分子会引发一系列分子变化，这种变化会随着时间的推移而扩展，即使治疗已经停止。
Activin/myostatin signalling acts to induce skeletal muscle atrophy in adult mammals by inhibiting protein synthesis as well as promoting protein and organelle turnover. Numerous strategies have been successfully developed to attenuate the signalling properties of these molecules, which result in augmenting muscle growth. However, these molecules, in particular activin, play major roles in tissue homeostasis in numerous organs of the mammalian body. We have recently shown that although the attenuation of activin/myostatin results in robust muscle growth, it also has a detrimental impact on the testis. Here, we aimed to discover the long-term consequences of a brief period of exposure to muscle growth-promoting molecules in the testis. We demonstrate that muscle hypertrophy promoted by a soluble activin type IIB ligand trap (sActRIIB) is a short-lived phenomenon. In stark contrast, short-term treatment with sActRIIB results in immediate impact on the testis, which persists after the sessions of the intervention. Gene array analysis identified an expansion in aberrant gene expression over time in the testis, initiated by a brief exposure to muscle growth-promoting molecules. The impact on the testis results in decreased organ size as well as quantitative and qualitative impact on sperm. Finally, we have used a drug-repurposing strategy to exploit the gene expression data to identify a compound – N6-methyladenosine – that may protect the testis from the impact of the muscle growth-promoting regime. This work indicates the potential long-term harmful effects of strategies aimed at promoting muscle growth by attenuating activin/myostatin signalling. Furthermore, we have identified a molecule that could, in the future, be used to overcome the detrimental impact of sActRIIB treatment on the testis. Editor’s choice: Brief exposure of the mouse testis to a muscle growth-promoting molecule initiates a cascade of molecular changes that expands over time, even when the treatment has stopped.
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