Skeletal Muscle Is a Novel Source of Fibroblast Growth Factor 23 (FGF-23) That Regulates Phosphate Homeostasis

Background: Fibroblast growth factor 23 (FGF23) is hormone that is secreted from bone in response to elevations in serum phosphate (Pi) levels (hyperphosphatemia) and that targets the kidney to increase Pi excretion. In chronic kidney disease (CKD), the kidney loses its ability to properly respond to FGF23 and to excrete Pi, leading to elevations in systemic levels of Pi and FGF23 which might contribute to various CKD-associated pathologies. Previous studies suggest that bone might not be the sole source for systemic FGF23 elevations. Here we determine whether mouse models of hyperphosphatemia express FGF23 in skeletal muscle (SM) and whether elevated Pi can induce FGF23 expression in cultured myotubes Methods: C2C12 and primary mouse and human myotubes were treated with increasing concentrations of Pi for 24 hours, followed by the analysis of FGF23 expression by qPCR and immunocytochemistry as well as ELISA from cell supernatants. We studied four mouse models of hyperphosphatemia: two CKD models, i.e. mice with deletion of collagen 4a3 and mice fed an adenine-rich diet for 14 weeks; and two non-CKD models: klotho deficient mice and mice fed a high-Pi diet for 6 months. Furthermore, we generated mice with SM-specific deletion of FGF23 (SM-FGF23-/-) and administered an adenine-rich or a high-Pi diet. We analyzed FGF23 production in SM tissue by qPCR, immunohistochemistry and ELISA as well as serum levels of FGF23 and Pi. We also injected SM-FGF23-/- with Pi and determined 24 hour urine excretion. Results: Pi treatments increase the expression and the secretion of FGF23 in MT in a dose-dependent manner. We could detect FGF23 expression in SM of all four mouse models on mRNA and protein level. SM-FGF23-/- on an adenine-rich or a high-Pi diet had significantly reduced FGF23 levels in SM and serum when compared to control mice on the same diet. SM-FGF23-/- mice on a high Pi diet also showed further elevations in serum Pi. Acute Pi load of SM-FGF23-/- mice resulted in reduced urine Pi levels. Conclusion: Hyperphosphatemia induces FGF23 expression in SM in the absence and presence of CKD. SM-derived FGF23 contributes to the pool of circulating FGF23 and seems to have physiologic activity by increasing renal Pi excretion. Funding: NIDDK Support