Spinal bulbar muscular atrophy (SBMA) is a progressive motor disease that appears only in men around mid-life and results in limb weakness, dysphagia (swallowing difficulties), and dysarthria (speech difficulties). The disease is believed to be neurogenic, originating from motoneuron dysfunction and its slow progressive death. Thus, most of the studies characterizing the disease in mice have focused on motoneuron as the site of disease although there is some clinical evidence suggesting... Show moreSpinal bulbar muscular atrophy (SBMA) is a progressive motor disease that appears only in men around mid-life and results in limb weakness, dysphagia (swallowing difficulties), and dysarthria (speech difficulties). The disease is believed to be neurogenic, originating from motoneuron dysfunction and its slow progressive death. Thus, most of the studies characterizing the disease in mice have focused on motoneuron as the site of disease although there is some clinical evidence suggesting skeletal muscle may be an important site of disease. SBMA is caused by a mutation that leads to an expansion of CAG repeats coding for glutamine in the androgen receptor (AR) gene, and the male-specific phenotype is believed to be androgen-dependent as females carrying the mutation have little to no symptoms. The male-specific disease phenotype has been replicated in mouse models expressing similar mutations and can be improved with castration, reinforcing that the disease is androgen-dependent. Furthermore, female mice in these models are asymptomatic and only exhibit disease symptoms with androgen treatment. Although a CAG expansion in the AR gene is thought to underlie the disease, a similar phenotype is observed in a transgenic (Tg) mouse line engineered to express a rat AR cDNA with a wild type (WT) number of glutamine residues (22) at very high levels exclusively in skeletal muscle fibers. Although alteration of gene and protein expression is exclusive to the skeletal muscles, mice from this myogenic (141) model exhibit a phenotype similar to the other CAG-expanded mouse models of SBMA. Tg 141 female mice that exhibit an androgen-dependent loss of motor function after 3-5 days of testosterone (T) treatment exhibit skeletal muscle dysfunction, recorded by electrically stimulating isolated preparations of the extensor digitorum longus (EDL) and the soleus (SOL), prototypical fast- and slow-twitch muscles, respectively. T treatment in female 141 Tg mice over 3-5 days was enough to induce a precipitous decrease in force production in both muscles and alterations to kinetics during contractions in the EDL. To confirm that skeletal muscles could be a primary site of disease during SBMA, male mice of the same 141 model, as well as two other SBMA mouse models were examined. The other models were one expressing the full-length human AR with 97 CAG repeats (97Q model) and another expressing 113 CAG repeats in the first exon of the AR gene. Muscle dysfunction in the other models would further support myogenic contributions as being critical to the SBMA motor phenotype. Motor dysfunction was recorded in all mouse models, and male mice from the 141 and 97Q models exhibited dysfunction in the EDL and SOL. All muscles exhibited some deficit during force production, and contraction kinetics were altered in the EDL of Tg 141 males. These results indicate that severe muscle dysfunction can underlie the phenotype during SBMA, and androgens can act on the skeletal muscles to induce motor weakness. Furthermore, skeletal muscles may be an important target for therapeutics that could ameliorate disease symptoms. Show less
