Abstract/Summary

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.