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Abstract: FR-OR04

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

Session Information

Category: Bone and Mineral Metabolism

  • 401 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
  • Campos, Isaac D., 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
  • Westbrook, David Gibbs, 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
  • Faul, Christian, The University of Alabama at Birmingham Department of Cell Developmental and Integrative Biology, Birmingham, Alabama, United States
Background

Chronic Kidney Disease (CKD) effects various tissues and is associated with elevated serum levels of fibroblast growth factor 23 (FGF23) and phosphate (Pi). FGF23 is a hormone that is produced by the bone and targets the kidney to regulate Pi homeostasis. Since Pi is a potent inducer of FGF23 expression in bone, we studied whether Pi can induce FGF23 production in skeletal muscle (SM), and potentially contribute to atrophy. We analyzed SM on a functional, histological and molecular level in four models of hyperphosphatemia – two CKD models, i.e. mice with global deletion of collagen 4a3 and wildtype mice receiving an adenine-rich diet, as well as wildtype mice on a high Pi diet with normal kidney function, and klotho deficient mice. Finally, we determined the effect of a low Pi diet on SM in Col4a3-/- mice.

Methods

C2C12 myotubes were treated with 1-5 mM Pi for 24 hours, followed by qPCR expression analysis of FGF23 and atrophy genes. We studied Col4a3-/- mice receiving normal chow or a 0.2% phosphate diet at 10 weeks age; C57Bl/6 mice receiving an adenine-rich (0.2%) diet for 14 weeks or 3% phosphate diet for 6 months, and klotho deficient mice. We analyzed grip strength, hindlimb area by MRI, muscle mass, cross-sectional area of muscle fibers, and expression levels of atrogenes by qPCR and of FGF23 by qPCR, ELISA, and immunofluorescence microscopy

Results

Pi treatments increased the expression levels of atrogenes and FGF23 in C2C12 myotubes. In the four mouse models, grip strength was significantly reduced. In CKD and klotho deficient mice, muscle mass, cross-sectional area of myofibers was reduced, and the expression levels of atrogenes were elevated when compared to respective controls. Furthermore, we detected elevations in the mRNA and protein levels of FGF23 in the hindlimb muscles of all models. Administration of a low Pi diet protected Col4a3-/- mice from developing SM atrophy.

Conclusion

Elevated Pi induces myotube atrophy and FGF23 expression in vitro. Mouse models with hyperphosphatemia develop SM atrophy and produce FGF23 in SM tissue in the presence and absence of CKD. Administration of a low Pi diet protects the SM in CKD mice. Future studies need to determine whether SM-derived FGF23 contributes to tissue injury or is protective against phosphate-induced damage.

Funding

  • NIDDK Support