Figure 2.

Pre-pubertal castration largely prevents pathological change in mRNA expression in AR97Q adult muscle. (A) The disease-related deficit in adult isoforms, AChR-ε subunit and sodium channel Nav1.4, are completely rescued by castration. Castration also largely reversed the disease-related increase in expression of mRNA for neonatal isoforms AChR-γ and Nav1.5, which underlie the slowed kinetics of EPPs and mEPPs and resistance to µ-CTX in disease, respectively. However, note small but significant increases in the expression of both AChR-γ and Nav1.5, apparently emerging sometime after castration (Fig. 3) independent of circulating gonadal androgens. Evidently the system can tolerate some level of pathological expression of the immature isoforms without affecting mEPP and EPP kinetics, likely reflecting which subunit (adult versus immature) predominates at any given time. (B) Similarly, mRNA expression for the Clcn1, and transcripts for the inward rectifying potassium channel (Kir2.1 and 2.2), and sodium/potassium pump (NKA a1 and a2) were all restored to normal by pre-pubertal castration of Tg males, consistent with the significant rescue of the RMP (Fig. 1). These data show that disease-related changes in the expression of muscle genes for ion channels and ion transporters underlying muscle and synaptic function are largely androgen-dependent, correlating well with the androgen-dependent loss of motor function in this SBMA model. Nonetheless, it also appears that mutant AR has the capacity to trigger subclinical symptoms of disease. Values are mean fold changes ± SEMs (standard errors of the mean) relative to WT + S values based on N/group (WT + S, WT + C and Tg + S: N = 7; Tg + C: N = 8). *P < 0.05 from WT sham or WT castrated; ^#P < 0.05 from Tg sham. ‘S’ denotes sham castration; ‘C’ denotes castration.