Advisor(s)
Stefanie Krick
Committee Member(s)
Christian Faul
Glenn Rowe
Matthew Alexander
Orlando Gutierrez
School
Joint Health Sciences (Interdisciplinary)
Document Type
Dissertation
Department (new version)
Cellular and Molecular Physiology
Date of Award
6-6-2025
Abstract
Chronic kidney disease (CKD) is a major public health issue often accompanied by various pathologies. Hyperphosphatemia contributes to a range of complications, including vascular calcification, systemic inflammation, anemia, left ventricular hypertrophy, and skeletal muscle atrophy. Phosphate homeostasis is tightly regulated through a combination of renal excretion and its storage in bones, with fibroblast growth factor (FGF) 23 playing a central role in this regulation. Produced primarily by osteocytes in response to elevated serum phosphate, FGF23 helps maintain phosphate balance by promoting renal phosphate excretion and inhibiting the synthesis of vitamin D and parathyroid hormone. Dysregulation of FGF23 is associated both genetic conditions, such as xlinked hypophosphatemic rickets, and the pathophysiology of CKD. This study investigates the effects of hyperphosphatemia on skeletal muscle across four mouse models including two CKD models (adenine diet and Col4a3-/-) and two non-CKD models (klotho deficient and high phosphate diet). In these mice, we assessed skeletal muscle inflammation, fibrosis, fat deposition, atrophy, and FGF23. Our findings indicate that elevated phosphate can contribute to skeletal muscle atrophy in mice, and directly induce atrophy in myotubes, highlighting a direct pathogenic effect of phosphate on muscle cells. Furthermore, our results indicate that elevated phosphate enhances FGF23 expression in skeletal muscle, and that FGF23 knockout mice exhibit impaired phosphate excretion, higher serum phosphate, and exacerbated muscle atrophy, particularly in the high phosphate diet mice. Collectively, this research suggests that skeletal muscle-derived FGF23 plays a physiological role in phosphate regulation, and offers minor protection against phosphate-induced atrophy. These findings provide insights into the interplay between phosphate homeostasis and muscle health with implications for conditions like CKD.
ProQuest ID
Recommended Citation
Heitman, Kylie, "The Bone Is Not Alone: Skeletal Muscle Is A Novel Source Of Fibroblast Growth Factor 23" (2025). All ETDs from UAB. 7317.
https://digitalcommons.library.uab.edu/etd-collection/7317
