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


https://doi.org/10.4081/ejtm.2019.8737
Vol. 30 No. 1 (2020)
Published: 1 April 2020
Muscle hypertrophy, Activin, Myostatin, adverse effects, neuromuscular diseases, Mossman-Pacey paradox, testis
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Authors

  • Danielle Vaughan School of Biological Sciences, University of Reading, United Kingdom.
  • Olli Ritvos Department of Bacteriology and Immunology, University of Helsinki, Helsinki, Finland.
  • Robert Mitchell School of Biological Sciences, University of Reading, United Kingdom.
  • Oliver Kretz III Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, United Kingdom.
  • Maciej Lalowski Department of Biochemistry and Developmental Biology, HiLIFE, Meilahti Clinical Proteomics Core Facility, University of Helsinki, Helsinki, Finland.
  • Helge Amthor Versailles Saint-Quentin-en-Yvelines University, INSERM U1179, LIA BAHN CSM, Montigny-le-Bretonneux, France.
  • David Chambers Functional Genomics, King’s college, London, United Kingdom.
  • Antonios Matsakas Molecular Physiology Laboratory, Centre for Atherothrombosis and Metabolic Disease, Hull York Medical School, Hull, United Kingdom.
  • Arja Pasternack Department of Bacteriology and Immunology, University of Helsinki, Helsinki, Finland.
  • Henry Collins-Hooper School of Biological Sciences, University of Reading, United Kingdom.
  • Randy Ballesteros Royal Veterinary College, London, United Kingdom.
  • Tobias B. Huber III Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  • Bernd Denecke RWRTH Aachen University, Aachen, Germany.
  • Darius Widera School of Pharmacy, University of Reading, United Kingdom.
  • Abir Mukherjee Royal Veterinary College, London, United Kingdom.
  • Ketan Patel
    ketan.patel@reading.ac.uk
    School of Biological Sciences, University of Reading, Reading, United Kingdom.

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.


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Robert Mitchell, School of Biological Sciences, University of Reading

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Oliver Kretz, III Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg

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Helge Amthor, Versailles Saint-Quentin-en-Yvelines University, INSERM U1179, LIA BAHN CSM, Montigny-le-Bretonneux

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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

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