A muscle growth-promoting treatment based on the attenuation of activin/myostatin signalling results in long-term testicular abnormalities

Vaughan, Danielle; Mitchell, Robert; Kretz, Oliver; Chambers, David; Lalowski, Maciej; Amthor, Helge; Ritvos, Olli; Pasternack, Arja; Matsakas, Antonios; Vaiyapuri, Sakthivel; Huber, Tobias B.; Denecke, Bernd; Mukherjee, Abir; Widera, Darius; Patel, Ketan

Abstract

© 2021. Published by The Company of Biologists Ltd. 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.

Citation

Vaughan, D., Mitchell, R., Kretz, O., Chambers, D., Lalowski, M., Amthor, H., …Patel, K. (2021). A muscle growth-promoting treatment based on the attenuation of activin/myostatin signalling results in long-term testicular abnormalities. Disease Models and Mechanisms, 14(2), Article dmm047555. https://doi.org/10.1242/dmm.047555

• Journal Article Type: Article
• Acceptance Date: Dec 22, 2020
• Online Publication Date: Feb 19, 2021
• Publication Date: 2021-02
• Deposit Date: Jun 3, 2021
• Publicly Available Date: Jun 3, 2021
• Journal: Disease models & mechanisms
• Print ISSN: 1754-8403
• Electronic ISSN: 1754-8411
• Publisher: The Company of Biologists
• Peer Reviewed: Peer Reviewed
• Volume: 14
• Issue: 2
• Article Number: dmm047555
• DOI: https://doi.org/10.1242/dmm.047555
• Keywords: Activin; Gene array; Muscle; Myostatin; Testis
• Public URL: https://hull-repository.worktribe.com/output/3742693