Myostatin regulates the production of fibroblast growth factor 23 (FGF23) in UMR106 osteoblast\u2013like cells

Franz Ewendt,Michael Föller,Martina Feger

doi:10.1007/s00424-021-02561-y

Abstract

Myostatin is a signaling molecule produced by skeletal muscle cells (myokine) that inhibits muscle hypertrophy and has further paracrine and endocrine effects in other organs including bone. Myostatin binds to activin receptor type 2B which forms a complex with transforming growth factor-β type I receptor (TGF-βRI) and induces intracellular p38MAPK and NFκB signaling. Fibroblast growth factor 23 (FGF23) is a paracrine and endocrine mediator produced by bone cells and regulates phosphate and vitamin D metabolism in the kidney. P38MAPK and NFκB-dependent store-operated Ca2+ entry (SOCE) are positive regulators of FGF23 production. Here, we explored whether myostatin influences the synthesis of FGF23. Fgf23 gene expression was determined by qRT-PCR and FGF23 protein by ELISA in UMR106 osteoblast–like cells. UMR106 cells expressed activin receptor type 2A and B. Myostatin upregulated Fgf23 gene expression and protein production. The myostatin effect on Fgf23 was significantly attenuated by TGF-βRI inhibitor SB431542, p38MAPK inhibitor SB202190, and NFκB inhibitor withaferin A. Moreover, SOCE inhibitor 2-APB blunted the myostatin effect on Fgf23. Taken together, myostatin is a stimulator of Fgf23 expression in UMR106 cells, an effect at least partially mediated by downstream TGF-βRI/p38MAPK signaling as well as NFκB-dependent SOCE.

Highlights

Myostatin is part of a group of signaling molecules produced by skeletal muscle cells that are known under the name “myokines” in analogy to “cytokines” [25]
The impact of myostatin on Fgf23 expression was studied in UMR106 osteoblast–like cells
This study provides evidence that myostatin, a signaling molecule produced by skeletal muscle cells, is a potent regulator of the production of Fibroblast growth factor 23 (FGF23), a hormone produced by bone cells

Summary

Introduction

Myostatin is part of a group of signaling molecules produced by skeletal muscle cells (myocytes) that are known under the name “myokines” in analogy to “cytokines” [25]. It was discovered in 1997 as a member of the TGF-β superfamily and first named “growth differentiation factor 8 (GDF-8)” [33]. The Belgian Blue, cattle with a loss of function mutation in the gene encoding myostatin, is characterized by enormous muscle mass [16, 25]. Mutations in the human gene encoding myostatin, which result in muscle hypertrophy, are described [25, 41]. The myokine myostatin plays a role as regulatory molecule in the crosstalk between muscle and bone [25, 29]

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Conclusion