Inhibition of Activin/Myostatin signalling induces skeletal muscle hypertrophy but impairs mouse testicular development

Vaughan, Danielle; Ritvos, Olli; Mitchell, Robert; Kretz, Oliver; Lalowski, MacIej; Amthor, Helge; Chambers, David; Matsakas, Antonios; Pasternack, Arja; Collins-Hooper, Henry; Ballesteros, Randy; Huber, Tobias B.; Denecke, Bernd; Widera, Darius; Mukherjee, Abir; Patel, Ketan

Abstract

© 2020 PAGEPress Publications. All rights reserved. Numerous approaches are being developed to promote post-natal muscle growth based on attenuating Myostatin/Activin signalling for clinical uses such as the treatment neuromuscular diseases, cancer cachexia and sarcopenia. However there have been concerns about the effects of inhibiting Activin on tissues other than skeletal muscle. We intraperitoneally injected mice with the Activin ligand trap, sActRIIB, in young, adult and a progeric mouse model. Treatment at any stage in the life of the mouse rapidly increased muscle mass. However at all stages of life the treatment decreased the weights of the testis. Not only were the testis smaller, but they contained fewer sperm compared to untreated mice. We found that the hypertrophic muscle phenotype was lost after the cessation of sActRIIB treatment but abnormal testis phenotype persisted. In summary, attenuation of Myostatin/Activin signalling inhibited testis development. Future use of molecules based on a similar mode of action to promote muscle growth should be carefully profiled for adverse side-effects on the testis. However the effectiveness of sActRIIB as a modulator of Activin function provides a possible therapeutic strategy to alleviate testicular seminoma development.

Citation

Vaughan, D., Ritvos, O., Mitchell, R., Kretz, O., Lalowski, M., Amthor, H., Chambers, D., Matsakas, A., Pasternack, A., Collins-Hooper, H., Ballesteros, R., Huber, T. B., Denecke, B., Widera, D., Mukherjee, A., & Patel, K. (2020). Inhibition of Activin/Myostatin signalling induces skeletal muscle hypertrophy but impairs mouse testicular development. European Journal of Translational Myology, 30(1), 62-78. https://doi.org/10.4081/ejtm.2019.8737

• Journal Article Type: Article
• Acceptance Date: Dec 5, 2019
• Online Publication Date: Apr 1, 2020
• Publication Date: Apr 7, 2020
• Deposit Date: Jan 26, 2021
• Publicly Available Date: Jan 29, 2021
• Journal: European Journal of Translational Myology
• Print ISSN: 2037-7452
• Electronic ISSN: 2037-7460
• Publisher: PAGEpress
• Peer Reviewed: Peer Reviewed
• Volume: 30
• Issue: 1
• Pages: 62-78
• DOI: https://doi.org/10.4081/ejtm.2019.8737
• Keywords: Muscle hypertrophy; Activin; Myostatin; Adverse effects; Neuromuscular diseases; Mossman-Pacey paradox; Testis
• Public URL: https://hull-repository.worktribe.com/output/3664525
• Publisher URL: https://pagepressjournals.org/index.php/bam/article/view/8737