Overexpression of wild-type androgen receptor in muscle recapitulates polyglutamine disease.

ABSTRACT: We created transgenic mice that overexpress WT androgen receptor (AR) exclusively in their skeletal muscle fibers. Unexpectedly, these mice display androgen-dependent muscle weakness and early death, show changes in muscle morphology and gene expression consistent with neurogenic atrophy, and exhibit a loss of motor axons. These features reproduce those seen in models of Kennedy disease, a polyglutamine expansion disorder caused by a CAG repeat expansion in the AR gene. These findings demonstrate that toxicity in skeletal muscles is sufficient to cause motoneuron disease and indicate that overexpression of the WT AR can exert toxicity comparable with the polyglutamine expanded protein. This model has two clear implications for Kennedy disease: (i) mechanisms affecting AR gene expression may cause neuromuscular symptoms similar to those of Kennedy disease and (ii) therapeutic approaches targeting skeletal muscle may provide effective treatments for this disease.

SUBMITTER: Monks DA 

PROVIDER: S-EPMC2084330 | biostudies-literature | 2007 Nov

REPOSITORIES: biostudies-literature