Testosteroneandsynthetic anabolic steroids are modifiers for mutant SOD1-related als pathogenesis

Background: Evidence indicates a higher incidence of spo- radic ALS (sALS) in males than in females. This difference is very marked in juvenile forms of ALS, but it declines with age, when androgen levels in the serum decrease. Varsity athletes, such as Italian soccer and American football players, and military veterans show a higher risk of developing ALS. Endogenous androgens act on the androgen receptor (AR), and anabolic synthetic steroids, such as nandrolone decanoate, are androgenic compounds illegally used as performance- enhancing agents.This suggests a possible correlation between the risk of developing SALS and dysregulation of androgen signalling. Objective: To verify this hypothesis, we tested the impact of androgen signalling in the pathogenesis of SOD1-related ALS in transgenic mice expressing mutant SOD1G93A. Mice were either castrated to eliminate serum androgens or treated with nandrolone decanoate to mimic the condition occurring in doped athletes. Results: Castration resulted in a significant decrease in body weight of SOD1G93A mice, but it enhanced muscle strength and motor coordination in ALS-affected mice. Castration also resulted in delayed disease onset and increased survival, although there was no significant effect on disease progres- sion. Castration was associated with decreased levels of expression of AR. On the other hand, treatment of intact mice with nandrolone did not affect the body weight of SOD1G93A mice, but it resulted in significant improvement in muscle strength and motor coordination. Nandrolone treatment did not affect disease onset and progression, though it increased survival compared to that of control mice. Nandrolone treat- ment resulted in increased EDL weight, strength and specific force, which was associated with an increase in speed contrac- tion. However, nandrolone effects were also associated with increased fatigue. Surprisingly, treatment of castrated mice with nandrolone deteriorated phenotype, and this was associ- ated with increased AR aggregation. Altogether, these results indicate that androgen signalling plays a role in SOD1-related ALS pathogenesis.