The proposed research seeks to understand the contribution of androgen receptor function in skeletal muscle fibers to neuromuscular development and function. Current opinion holds that androgen receptor exerts an anabolic effect on muscle fibers. Contrary to this view, the PI has recently discovered that mice that over-express androgen receptor in muscle fibers develop androgen-dependent muscle wasting (muscular atrophy) and locomotor deficits. The proposed research is a characterization of this muscular atrophy as well as an investigation of its endocrine and molecular basis. The first specific aim examines whether the observed muscular atrophy results in degeneration or death of the motoneurons that innervate these muscles. The subsequent specific aims investigate the contribution of androgenic signaling to the muscular atrophy using endocrine, pharmacological and genetic manipulations of androgen metabolism and androgen receptor function. The proposed research is expected to be beneficial because muscular atrophy is a debilitating aspect of diverse clinical disorders, including spinal and bulbar muscular atrophy (SBMA, also known as Kennedy's disease), a disorder caused by mutant androgen receptors. Because there is currently no effective therapeutic strategy for managing SBMA, investigating the roles of androgen receptor in muscular atrophy may yield valuable insights into potential interventions for this disorder. Furthermore, these studies are expected to increase our understanding of how androgens influence the size and strength of skeletal muscles. ? ?
