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Inorganic phosphate (Pi) is used in high amounts as a preservative in the Western diet, but the effects of Pi on metabolism and gene expression have not been investigated. We previously observed that high serum phosphate levels are associated with low physical activity in humans, and we demonstrated that high phosphate diet decreases exercise capacity in male mice. However, the mechanisms responsible for high phosphate-impaired exercise remain unknown. Our hypothesis is that high phosphate diet alters gene expression in skeletal muscle, which affects muscle function and metabolism, and contributes to decreased exercise capacity. We used C2C12 myoblasts and myotubes as an in vitro model system to study the effects of high phosphate on gene expression in muscle cells. During C2C12 myoblast differentiation, we cultured cells with normal phosphate (NP, 1mM) or high phosphate (HP, 3mM) media. Myoblasts and myotubes were collected at day 0, 1, 3, 5, and 7 of differentiation with NP or HP media, RNA was isolated and muscle differentiation and metabolism genes were quantified using qPCR. We observed a downregulation of genes involved in fatty acid synthesis, release, and oxidation such as mPgk1 and mFabp4. In addition, glucose metabolism genes such as mLdha were upregulated. However, we did not observe changes in differentiation of C2C12 myoblasts or expression of muscle differentiation genes. We also studied the effect of a high phosphate diet in vivo. Male mice were fed a normal phosphate diet (0.6% Pi) or high phosphate diet (2.0% Pi) and,after 19 weeks, the tissues were harvested. Metabolic genes that control fatty acid metabolism were dysregulated in skeletal muscle, but we did not detect differences in fatty acid metabolism gene expression in the liver. The data suggests that high phosphate has a detrimental effect on metabolic gene regulation in myotubes, which could potentially lead to decreased exercise capacity. Future studies will determine whether the negative effects of inorganic phosphate are reversible or time dependent. We will also investigate the mechanisms regulating high phosphate-induced changes in gene expression.