Endocrine Abstracts

Background: Hypogonadism in men is associated with low muscle mass and force. Although, androgen replacement is an effective therapy, it can have undesirable side effects. Identifying the androgen regulated molecular mechanisms that increase muscle mass and function could lead to the identification of novel muscle-specific therapeutic targets to improve the clinical outcomes of muscle wasting diseases. In this study, we examined in mice the effects of orchidectomy (after 1, 7 and 30 days), either with or without testosterone or estradiol (E₂) administration, on the muscle-specific ubiquitin protein ligases Atrogin-1, MuRF1 and myostatin gene and protein expression.

Methods: Measurements were made in slow-twitch soleus (SOL), fast-twitch extensor digitorum longus (EDL) and androgen-sensitive levator ani/bulbocavernosus (LA/BC) muscle of male C57BL/6 mice.

Results: Thirty days of orchidectomy was associated with a significant decrease in muscle strength and muscle mass in SOL (13.8%), EDL (12.9%) and LA/BC (63%). These effects were prevented by testosterone treatment. In the LA/BC muscle, Atrogin-1 and MuRF1 mRNA were increased throughout the 30 days of androgen deprivation, which was fully reversed by testosterone administration and partially reversed by E₂ administration. In SOL and EDL, a less pronounced upregulation of both genes was only detectable at the early stages of orchidectomy. Myostatin mRNA levels were upregulated in EDL. However, these changes were not paralleled by changes in the protein levels of Atrogin-1, MuRF1 and myostatin at any time point following orchidectomy. Our data indicate important differences in orchidectomy-induced skeletal muscle atrophy between LA/BC and the locomotor muscles.

Conclusion: These findings also question role of Atrogin-1, MuRF1 and myostatin in this model of muscle atrophy and suggest that other proteolytic targets are responsible for the loss in SOL and EDL muscles mass after androgen deprivation.