Androgens influence the survival and growth of a neuromuscular system, the spinal nucleus of the bulbocavernosus (SNB) and its target muscles, the levator ani (LA) and the bulbocavernosus (BC). Proposed experiments will test whether LA/BC muscle fibers are direct cellular targets for androgens. Focus will be on LA/BC muscle fibers as prime mediators of androgenic influences on the SNB system because 1) androgens act directly on LA/BC muscles to regulate their survival and growth, and the survival and growth of SNB motoneurons and 2) androgen receptors (ARs) are enriched in muscle fibers of the LA/BC compared to other skeletal muscles. Proposed experiments will utilize two newly created transgenic mouse models that either over or under express ARs in their muscle fibers. These two models will be used to evaluate whether ARs in muscle fibers are necessary and/or sufficient for androgens to rescue the SNB system from death in development and promote expression of calcitonin gene-related peptide by SNB motoneurons in adulthood. Transgenic males will be compared to controls males (wild-type males and/or males that have a dysfunctional AR gene) and standard cellular approaches will be applied to answer these questions. Finally, males in some transgenic lines that overexpress ARs in muscle fibers show a progressive, late-onset neuromuscular degenerative disease that mimics Spinal Bulbar Muscular Atrophy (SBMA), a neurodegenerative disease in humans caused by a mutation in the AR gene (expansion of CAG repeats). SBMA afflicts primarily men in mid-life. Some proposed experiments are aimed at characterizing the emergent phenotype and the underlying pathology of this disease, and its ligand-dependence using behavioral, cellular and molecular methods. Relevance: Despite the essential role motoneurons have in all aspects of human life, motoneurons are susceptible to disease, and undergo selective demise in diseases such as Spinal Bulbar Muscular Atrophy (SBMA) and Amyotrophic Lateral Sclerosis (ALS). As part of the normal course of development, androgenic hormones prevent some motoneurons from dying and curiously, these same motoneurons are selectively spared in SBMA and ALS. We propose to study transgenic mouse models that have an altered expression of androgen receptors in skeletal muscle fibers to better understand how hormones regulate the survival of motoneurons. ? ?
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