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Abstract: FR-PO296

Skeletal Muscle Is a Novel Source of FGF23 in Mouse Models of CKD

Session Information

Category: Bone and Mineral Metabolism

  • 501 Bone and Mineral Metabolism: Basic

Authors

  • Heitman, Kylie, The University of Alabama at Birmingham Department of Cell Developmental and Integrative Biology, Birmingham, Alabama, United States
  • Thomas, Madison, The University of Alabama at Birmingham Department of Cell Developmental and Integrative Biology, Birmingham, Alabama, United States
  • Fajol, Abul, The University of Alabama at Birmingham Department of Cell Developmental and Integrative Biology, Birmingham, Alabama, United States
  • Li, Qing, The University of Alabama at Birmingham Department of Cell Developmental and Integrative Biology, Birmingham, Alabama, United States
  • Komarova, Svetlana, The University of Alabama at Birmingham Department of Cell Developmental and Integrative Biology, Birmingham, Alabama, United States
  • Yanucil, Christopher, The University of Alabama at Birmingham Department of Cell Developmental and Integrative Biology, Birmingham, Alabama, United States
  • Alexander, Matthew S., The University of Alabama at Birmingham Department of Cell Developmental and Integrative Biology, Birmingham, Alabama, United States
  • Faul, Christian, The University of Alabama at Birmingham Department of Cell Developmental and Integrative Biology, Birmingham, Alabama, United States
Background

Fibroblast growth factor 23 (FGF23) increases renal phosphate (Pi) excretion, & beginning in early stages of CKD, FGF23 levels rise progressively in an attempt to maintain normal Pi levels. Pi is a potent inducer of FGF23 in bone. 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.

Methods

C2C12 MT & primary mouse MT were treated with 1-12 mM Pi for 24 hours, followed by qPCR expression analysis of FGF23. MT were grown in chamber-slides, treated with Pi, & immunostained with anti-FGF23. We analyzed four models of hyperphosphatemia: two CKD models, i.e. mice with global deletion of collagen 4a3 (Col4a3-/-) & wildtype mice receiving an adenine-rich (0.2%) diet for 14 weeks, & two non-CKD models--a klotho deficient mouse & wildtype mouse receiving a high Pi (3%) diet for 3 & 6 months. We also studied Col4a3-/- mice receiving a low Pi (0.2%) diet for 7 weeks. Furthermore, we generated mice with SM-specific deletion of FGF23 (FGF23fl/fl;HSA-Cre+) & administered an adenine-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.

Results

Pi treatments increased FGF23 expression in C2C12 MT & primary mouse MT in a dose-dependent manner. In all four mouse models we detected FGF23 in SM tissue on mRNA & protein level. When Col4a3-/- mice received a low Pi diet, FGF23 expression was reduced. 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.

Conclusion

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, & for example contributes to SM atrophy that we have detected in these mouse models. Furthermore, we will determine if SM-derived FGF23 has endocrine effects & increases renal Pi excretion.

Funding

  • NIDDK Support