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 while the attenuation of Activin/Myostatin results in robust muscle growth, it also has detrimental impact on the testis. Here, we aimed to discover the long-term consequences of a brief period of exposure to molecules that promote muscle on 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 identifies 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. Taken together, this work shows 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 future be used to overcome the detrimental impact of sActRIIB treatment on the testis.

中文翻译：

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基于年轻小鼠激活素/肌肉抑制素信号减弱的肌肉生长促进治疗会导致长期睾丸异常。

激活素/肌肉抑制素信号通过抑制蛋白质合成以及促进蛋白质和细胞器更新来诱导成年哺乳动物的骨骼肌萎缩。已经成功开发了许多策略来减弱这些分子的信号传导特性，从而促进肌肉生长。然而，这些分子，特别是激活素，在哺乳动物身体众多器官的组织稳态中发挥着重要作用。我们最近表明，虽然激活素/肌肉抑制素的衰减会导致肌肉强劲生长，但它也会对睾丸产生不利影响。在这里，我们旨在发现短期暴露于促进睾丸肌肉的分子的长期后果。我们证明由可溶性激活素 IIB 型配体陷阱 (sActRIIB) 促进的肌肉肥大是一种短暂的现象。与此形成鲜明对比的是，使用 sActRIIB 的短期治疗会对睾丸产生直接影响，这种影响在干预期后仍然存在。基因阵列分析确定了睾丸中异常基因表达随时间的扩大，这是由短暂暴露于肌肉生长促进分子引发的。对睾丸的影响导致器官大小的减小以及对精子的数量和质量的影响。最后，我们使用了药物再利用策略来利用基因表达数据来识别化合物 基因阵列分析确定了睾丸中异常基因表达随时间的扩大，这是由短暂暴露于肌肉生长促进分子引发的。对睾丸的影响导致器官大小的减小以及对精子的数量和质量的影响。最后，我们使用了药物再利用策略来利用基因表达数据来识别化合物 基因阵列分析确定了睾丸中异常基因表达随时间的扩大，这是由短暂暴露于肌肉生长促进分子引发的。对睾丸的影响导致器官大小的减小以及对精子的数量和质量的影响。最后，我们使用了药物再利用策略来利用基因表达数据来识别化合物N ⁶ -甲基腺苷，可以保护睾丸免受肌肉生长促进方案的影响。总之，这项工作显示了旨在通过减弱 Activin/Myostatin 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，该分子将来可用于克服 sActRIIB 治疗对睾丸的不利影响。