Skeletal muscle is a novel source of FGF23 in mouse models of chronic kidney disease

University of Alabama at Birmingham

Fibroblast growth factor 23 (FGF23) increases renal Pi excretion, & beginning in early stages of CKD, FGF23 levels rise progressively in an attempt to maintain normal Pi levels. Previous studies suggested that bone might not be the sole source for systemic FGF23 elevations in CKD. Here we study whether mouse models of hyperphosphatemia express FGF23 in skeletal muscle (SM) & whether Pi treatments of cultured myotubes (MT) induce FGF23 expression.C2C12 & primary mouse MT were treated with 1-12 mM Pi for 24 hours, followed analysis of FGF23 by qPCR, and immunostaining with anti-FGF23. We analyzed four models of hyperphosphatemia: two CKD models, i.e. a collagen 4a3 (Col4a3-/-) & mice fed an adenine diet & two non-CKD models--a klotho deficient mouse & mice fed a high Pi diet. Furthermore, we generated mice with SM-specific deletion of FGF23 (FGF23fl/fl;HSA-Cre+) & administered anadenine-rich or a high Pi diet for 14 weeks or 6 months, respectively. We studied FGF23 expression in SM by qPCR, ELISA & immunofluorescence microscopy, as well as serum levels of FGF23 & Pi.Pi treatments increased FGF23 expression MT in a dose-dependent manner. In four mouse models we detected FGF23 in SM tissue on mRNA & protein level. FGF23fl/fl;HSA-Cre+ mice on an adenine or a high Pi diet had significantly lower FGF23 mRNA & protein levels in SM & reduced serum FGF23 levels, when compared to control mice on the same diet.Mouse models with hyperphosphatemia produce FGF23 in SM tissue in the presence & absence of CKD. SM-derived FGF23 significantly contributes to the hyperphosphatemia-associated elevations in serum FGF23 levels. Our ongoing studies aim to determine whether SM-derived FGF23 has paracrine effects. Furthermore, we will determine if SM-derived FGF23 has endocrine effects & increases renal Pi excretion.