A long-standing and significant barrier to understanding the mechanisms behind Kennedy disease (KD) is the assumption that the agent of disease (a mutated androgen receptor (AR)) acts directly in motoneurons to cause their death. While skeletal muscle are also affected in KD, muscle atrophy and weakness was attributed to a loss of innervation; i.e., effects of disease on muscle was assumed to have a neurogenic cause. A transgenic (tg) mouse model developed to identify the cells that androgens act on to drive sexual differentiation of a neuromuscular system led to the serendipitous discovery that AR acts in muscle fibers (not motoneurons) to trigger KD. This finding has prompted a major paradigm shift in the field. Mouse models developed by other investigators since this discovery also conclude AR acts directly in muscle to cause KD, questioning whether AR in motoneurons has any role in this disease. The current proposed Aims continue to build on this new appreciation for muscle as a key player in KD, using an innovative systems approach and cross-model comparisons to identify critical mechanisms in muscle that directly impart disease to the muscle and indirectly to the motoneurons.
Aim 1 will extend pilot data using qPCR to further characterize the expression of neonatal isoforms of critical membrane channels and cytoskeletal proteins that control muscle contractile properties in diseased adult KD muscle.
Aim 2 will use classic physiological approaches to determine whether muscles are functionally denervated.
Aim 3 will continue efforts to test FDA approved AR antagonists as immediately available treatment options for KD patients by testing the AR antagonist bicalutamide which does not readily cross the blood-brain barrier in three KD mouse models.
Aim 4 will directly test whether brain-derived neurotrophic factor (BDNF) produced in skeletal muscle mediates motor dysfunction in KD using two in vivo complimentary approaches, 1) reversing a disease-related deficit in muscle BDNF via expression of a BDNF transgene in KD muscle and 2) disabling the endogenous BDNF gene in KD muscle. This last Aim takes advantage of floxed and cre recombinase mouse models that we have ready access to.
Kennedy's disease (KD) is a heritable neurodegenerative disease that disables middle-aged men but not women. Our studies of the first muscle-specific mouse model of KD make clear that the higher male levels of testosterone act on toxic androgen receptors in skeletal muscle to cause this disease. The proposed studies are aimed at understanding how androgen receptors in muscle impair muscle function directly and indirectly cause dysfunction and death of spinal motoneurons.
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