The loss of motor function that occurs with aging is closely associated with adverse health outcomes. In recent years, published findings strongly suggest that malfunction and degeneration of the neuromuscular junction (NMJ), the synapse formed between ?-motor neurons and skeletal muscle fibers, contributes to age-related motor dysfunction. As the final output of the somatic motor system, degeneration of the NMJ inevitably results in degeneration of motor axons and atrophy of muscle fibers, thus affecting voluntary movement. Thus, it is critical to identify factors that function to maintain and repair the NMJ. Using an R56 grant provided by NIA, our lab has identified the fibroblast growth factor binding protein 1 (FGFBP1) as a promising candidate factor secreted by muscle fibers to preserve and restore the integrity of NMJs during aging. FGFBP1 functions to chaperone FGF ligands from the extracellular matrix to cognate receptors. In this manner, it enhances FGF signaling. We have found that while FGFBP1 concentrates at NMJs in young adult mice, it progressively decreases during normal aging and in SOD1G93A mice, a mouse model for ALS. Using knockout mice, we observed that FGFBP1 expression is required to slow aging of NMJs and motor deficits during normal aging. Furthermore, FGFBP1 deletion in mice expressing SOD1G93A, a model for amyotrophic lateral sclerosis (ALS), accelerates NMJ degeneration, disease progression and death. These initial discoveries strongly suggest that preventing loss of endogenous of FGFBP1 during aging may be sufficient to slow degeneration of NMJs, and thus preserve motor function. To test this hypothesis, we proposed three specific aims that build on each other.
In aim 1, we test the hypothesis that motor deficits in mice deficient for FGFBP1 result from cellular, molecular, and physiological changes at NMJs.
In aim 2, we will seek to identify molecular mechanisms that inhibit FGFBP1 expression in aging muscles.
In aim 3, we will test the hypothesis that FGFBP1 is sufficient to prevent and reverse age-related changes of NMJs.
These aims are designed to uncover the initial changes that precipitate aging of NMs, the molecular factors that result in decreased FGFBP1 expression in aging muscle, and the therapeutic potential of FGFBP1 in preserving NMJs and motor function.
PHS Impact Statement Age and disease related motor deficits have proven to be quite costly in terms of quality of life and the resources required for medical care. The discovery of protective muscle- derived factors could form the basis to slow degeneration of muscles and their NMJs, and thus preserve and restore motor function during aging. Such factors may play a similar function in brain synapses during normal aging and progression of age-related brain disorders, including Alzheimer's disease.
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