"Muscle-derived neurotrophic factors are critical to the survival and maintenance of a healthy neuromuscular system and their expression is often perturbed in neuromuscular disease, such as in spinal bulbar muscular atrophy (SBMA). SBMA is a disease that occurs only in men, is androgen-dependent, and is characterized by the progressive weakness and atrophy of muscles that are innervated by lower motoneurons of the brain stem and spinal cord. Moreover, a polyglutamine expansion mutation in the androgen receptor (AR) gene is linked to SBMA. CHAPTER 1 provides a general introduction on SBMA pathophysiology, and describes the various implicated roles of neurotrophic factors in health and disease, with a particular emphasis on the role of brain-derived neurotrophic factor in the neuromuscular system. In this dissertation, I examine the status and potential contribution of muscle-derived brain-derived neurotrophic factor in SBMA pathogenesis using two mouse models of this disease. I conclude that supplementing diseased muscle with exogenous BDNF may offer therapeutic benefit for treating symptoms of SBMA. In CHAPTER 2, I describe my discovery that skeletal muscle from diseased SBMA mice were deficient in BDNF. I found this deficit in two different mouse models of SBMA (one that overexpresses wild-type AR in a muscle-specific manner as well as one that globally expresses a polyglutamine-expanded AR). I also found comparable deficits in BDNF in both fast and slow muscles. To explore whether the deficit in muscle BDNF is relevant to SBMA pathology, I asked whether it was androgen-dependent like the disease. Indeed, BDNF mRNA levels were reduced in the presence of androgens, correlating with motor dysfunction, and when androgens were removed, both BDNF expression and motor function were restored to normal. Moreover, I found that BDNF levels were reduced prior to the loss of motor function, thus indicating that impaired BDNF expression in skeletal muscles is an early and possibly precipitating event in the emergence of motor dysfunction in SBMA. In CHAPTER 3, I sought to examine whether relieving the deficit in muscle BDNF would ameliorate disease symptoms, given the strong correlation found in CHAPTER 2, as well as the substantial evidence linking BDNF to the maintenance of proper neuromuscular function. To do so, I used a transgenic Cre/loxP approach to specifically overexpress BDNF in muscle cells of diseased SBMA mice. I found that overexpression of muscle BDNF slowed disease progression after its onset, slowing the normal rate of decline in hang performance. Moreover, this improvement was associated with an improvement in the expression of genes relevant to muscle contraction in slow-twitch muscle, but not fast. CHAPTER 4 provides an overview of my findings and describes remaining questions and future work to be done. The approach to delineate which disease mechanisms are improved by muscle BDNF to slow disease progression will be discussed in CHAPTER 4. Candidate mechanisms include improved neuromuscular transmission and muscle contractile force tension in slow-twitch muscles."--Pages ii-iii.
Read
