Systemic Phosphate Elevations Induce Fibroblast Growth Factor 23 Production in Skeletal Muscle to Reduce Renal Phosphate Reabsorption in Mice

KEY POINTS: Our study identified skeletal muscle as a novel source of fibroblast growth factor 23 (FGF23) in scenarios of hyperphosphatemia, including high dietary phosphate intake and CKD. Skeletal muscle-derived FGF23 had endocrine actions lowering serum phosphate levels, which may protect from hyperphosphatemia-induced tissue damages. Skeletal muscle-derived FGF23 might also have paracrine effects counteracting atrophy. BACKGROUND: Fibroblast growth factor 23 (FGF23) is a hormone that reduces the renal reabsorption of phosphate in response to systemic phosphate elevations. In CKD, serum levels of phosphate and FGF23 reach levels that can harm various tissues. While the bone acts as the main production site for FGF23, bone-specific gene deletion studies in mice suggest the existence of other FGF23 sources. Here, we determine if skeletal muscle produces FGF23 in response to phosphate elevations. METHODS: We studied four mouse models with phosphate elevations, two with CKD (global Col4a3 deletion and adenine-rich diet) and two without CKD (genetic klotho deficiency and high-phosphate diet). Furthermore, we generated a new mouse line with skeletal muscle-specific Fgf23 deletion (KO), which received an adenine-rich or a high-phosphate diet. We measured skeletal muscle FGF23 by quantitative real-time PCR, ELISA, and immunohistochemistry, as well as serum levels of phosphate, FGF23, and parathyroid hormone (PTH). We determined FGF23 mRNA levels in muscle biopsies from patients with CKD, and we studied the effects of phosphate and PTH elevations on FGF23 expression in cultured myotubes isolated from mice and patients with CKD. Finally, we studied the effects of acute phosphate loading on urine phosphate levels in Fgf23 KO mice. RESULTS: All four mouse models with phosphate and PTH elevations showed FGF23 expression in skeletal muscle tissue on mRNA and protein level. Phosphate, but not PTH, induced FGF23 expression in cultured myotubes. Furthermore, patients with CKD with higher serum phosphate levels expressed more FGF23 in skeletal muscle. Fgf23 KO mice had elevated serum phosphate levels when administered a high-phosphate diet and decreased urine phosphate levels after acute phosphate loading. CONCLUSIONS: Phosphate elevations induced FGF23 expression in skeletal muscle, independent of the absence or presence of CKD. Skeletal muscle-derived FGF23 reduced renal phosphate reabsorption.