Fibroblast Growth Factor 23 and Muscle Wasting: A Metabolic Point of View

Abstract

Protein energy wasting (PEW), mostly characterized by decreased body stores of protein and energy sources, particularly in the skeletal muscle compartment, is highly prevalent in patients with moderate to advanced chronic kidney disease (CKD). Fibroblast growth factor 23 (FGF23) is an endocrine hormone secreted from bone and has systemic actions on skeletal muscle. In CKD, FGF23 is elevated and its coreceptor α-klotho is suppressed. Multiple lines of evidence suggest that FGF23 is interconnected with various mechanisms of skeletal muscle wasting in CKD, including systemic and local inflammation, exaggerated oxidative stress, insulin resistance (IR), and abnormalities in adipocytokine metabolism. Investigation of metabolic actions of FGF23 on muscle tissue could provide new insights into metabolic and nutritional abnormalities observed in patients with CKD. Protein energy wasting (PEW), mostly characterized by decreased body stores of protein and energy sources, particularly in the skeletal muscle compartment, is highly prevalent in patients with moderate to advanced chronic kidney disease (CKD). Fibroblast growth factor 23 (FGF23) is an endocrine hormone secreted from bone and has systemic actions on skeletal muscle. In CKD, FGF23 is elevated and its coreceptor α-klotho is suppressed. Multiple lines of evidence suggest that FGF23 is interconnected with various mechanisms of skeletal muscle wasting in CKD, including systemic and local inflammation, exaggerated oxidative stress, insulin resistance (IR), and abnormalities in adipocytokine metabolism. Investigation of metabolic actions of FGF23 on muscle tissue could provide new insights into metabolic and nutritional abnormalities observed in patients with CKD. Patients with CKD display a certain form of nutritional and metabolic abnormality suitably called PEW.1Fukasawa H. Ishigaki S. Kinoshita-Katahashi N. et al.Plasma levels of fibroblast growth factor-23 are associated with muscle mass in haemodialysis patients.Nephrol (Carlton). 2014; 19: 784-790https://doi.org/10.1111/nep.12333Crossref PubMed Scopus (13) Google Scholar Presence and severity of PEW is highly predictive of short-term and long-term morbidity and mortality among patients with all stages of CKD.2Ikizler T.A. Nutrition, inflammation and chronic kidney disease.Curr Opin Nephrol Hypertens. 2008; 17: 162-167https://doi.org/10.1097/MNH.0b013e3282f5dbceCrossref PubMed Scopus (55) Google Scholar PEW of CKD is usually characterized by decreased body stores of protein and energy. Detailed studies of protein metabolism suggest that there is relatively increased protein breakdown relative to protein anabolism, particularly in the skeletal muscle compartment.3Yu M.-D. Zhang H.-Z. Zhang Y. et al.Relationship between chronic kidney disease and sarcopenia.Sci Rep. 2021; 11: 20523https://doi.org/10.1038/s41598-021-99592-3Crossref PubMed Scopus (11) Google Scholar These abnormalities are observed in almost 20% of patients with stage 3 to 5 CKD who are not on maintenance dialysis, and the prevalence sharply increases to more than 55% once the patients initiate on maintenance dialysis, regardless of the dialytic modality. FGF23 belongs to the FGF family of polypeptides and is shown to play an important role in bone and mineral metabolism in patients with CKD. FGF23 and its coreceptor klotho deficiency or mutations are characterized by severe muscle wasting in animal models.4Hesse M. Fröhlich L.F. Zeitz U. Lanske B. Erben R.G. Ablation of vitamin D signaling rescues bone, mineral, and glucose homeostasis in Fgf-23 deficient mice.Matrix Biol. 2007; 26: 75-84https://doi.org/10.1016/j.matbio.2006.10.003Crossref PubMed Scopus (158) Google Scholar, 5Ohnishi M. Nakatani T. Lanske B. Razzaque M.S. Reversal of mineral ion homeostasis and soft-tissue calcification of klotho knockout mice by deletion of vitamin D 1alpha-hydroxylase.Kidney Int. 2009; 75: 1166-1172https://doi.org/10.1038/ki.2009.24Abstract Full Text Full Text PDF PubMed Scopus (161) Google Scholar, 6Nakatani T. Sarraj B. Ohnishi M. et al.In vivo genetic evidence for klotho-dependent, fibroblast growth factor 23 (FGF23) -mediated regulation of systemic phosphate homeostasis.FASEB J. 2009; 23: 433-441https://doi.org/10.1096/fj.08-114397Crossref PubMed Scopus (211) Google Scholar, 7Ohnishi M. Razzaque M.S. Dietary and genetic evidence for phosphate toxicity accelerating mammalian aging.FASEB J. 2010; 24: 3562-3571https://doi.org/10.1096/fj.09-152488Crossref PubMed Scopus (208) Google Scholar, 8Kurosu H. Yamamoto M. Clark J.D. et al.Suppression of aging in mice by the hormone klotho.Science. 2005; 309: 1829-1833https://doi.org/10.1126/science.1112766Crossref PubMed Scopus (1409) Google Scholar, 9Shimada T. Kakitani M. Yamazaki Y. et al.Targeted ablation of FGF23 demonstrates an essential physiological role of FGF23 in phosphate and vitamin D metabolism.J Clin Invest. 2004; 113: 561-568https://doi.org/10.1172/JCI19081Crossref PubMed Scopus (0) Google Scholar, 10Razzaque M.S. Sitara D. Taguchi T. St-Arnaud R. Lanske B. Premature aging-like phenotype in fibroblast growth factor 23 null mice is a vitamin D-mediated process.FASEB J. 2006; 20: 720-722https://doi.org/10.1096/fj.05-5432fjeCrossref PubMed Scopus (302) Google Scholar, 11Kuro-o M. Klotho.Pflugers Arch. 2010; 459: 333-343https://doi.org/10.1007/s00424-009-0722-7Crossref PubMed Scopus (203) Google Scholar In this article, we review the metabolic actions of FGF23 on skeletal muscle tissue and explore the interconnections between FGF23 and known mechanisms of skeletal muscle wasting in the setting of CKD. The FGF family is composed of polypeptides, which have critical biologic functions such as cell growth, differentiation, angiogenesis, embryonic development, wound healing, repair, and metabolic function. There are 18 mammalian FGFs (FGF1–FGF10 and FGF16–FGF23).12Beenken A. Mohammadi M. The FGF family: biology, pathophysiology and therapy.Nat Rev Drug Discov. 2009; 8: 235-253https://doi.org/10.1038/nrd2792Crossref PubMed Scopus (1391) Google Scholar Majority of FGFs act as autocrine and paracrine proteins (canonical FGFs) with 4 tyrosine kinase receptors [FGF receptor (FGFR) 1–4)].13Degirolamo C. Sabbà C. Moschetta A. Therapeutic potential of the endocrine fibroblast growth factors FGF19, FGF21 and FGF23.Nat Rev Drug Discov. 2016; 15: 51-69https://doi.org/10.1038/nrd.2015.9Crossref PubMed Scopus (283) Google Scholar They bind FGFRs with quite low affinity and require transmembrane glycoproteins, α-klotho and β-klotho, as coreceptors in their respective tissues to activate their cognate FGFRs.12Beenken A. Mohammadi M. The FGF family: biology, pathophysiology and therapy.Nat Rev Drug Discov. 2009; 8: 235-253https://doi.org/10.1038/nrd2792Crossref PubMed Scopus (1391) Google Scholar, 13Degirolamo C. Sabbà C. Moschetta A. Therapeutic potential of the endocrine fibroblast growth factors FGF19, FGF21 and FGF23.Nat Rev Drug Discov. 2016; 15: 51-69https://doi.org/10.1038/nrd.2015.9Crossref PubMed Scopus (283) Google Scholar, 14Mace M.L. Olgaard K. Lewin E. New aspects of the kidney in the regulation of fibroblast growth factor 23 (FGF23) and mineral homeostasis.Int J Mol PubMed Scopus Google Scholar There are known of in the and β-klotho, which is in various metabolic M. Klotho.Pflugers Arch. 2010; 459: 333-343https://doi.org/10.1007/s00424-009-0722-7Crossref PubMed Scopus (203) Google S. et of endocrine 2021; PubMed Scopus Google M. C. et vitamin and the and the of J Clin Scopus Google Scholar FGFs have a role in vitamin D and phosphate in and metabolic C. Sabbà C. Moschetta A. Therapeutic potential of the endocrine fibroblast growth factors FGF19, FGF21 and FGF23.Nat Rev Drug Discov. 2016; 15: 51-69https://doi.org/10.1038/nrd.2015.9Crossref PubMed Scopus (283) Google Scholar In and are in skeletal muscle from of and play a role in skeletal muscle M. and of fibroblast growth factor receptors in the PubMed Scopus Google Scholar FGF23 is a with a of The of FGF23 is the a cell from that in is by protein C. Sabbà C. Moschetta A. Therapeutic potential of the endocrine fibroblast growth factors FGF19, FGF21 and FGF23.Nat Rev Drug Discov. 2016; 15: 51-69https://doi.org/10.1038/nrd.2015.9Crossref PubMed Scopus (283) Google H. M. The role of FGF23 in or Rev 8: PubMed Scopus Google Scholar, H. M. more than a of phosphate 2010; PubMed Scopus Google Scholar, M.S. wasting and fibroblast growth Opin 20: PubMed Scopus Google Scholar The protein is and its in vivo in of and FGF23 the to bind to functions as a FGF23 M.L. Olgaard K. Lewin E. New aspects of the kidney in the regulation of fibroblast growth factor 23 (FGF23) and mineral homeostasis.Int J Mol PubMed Scopus Google Scholar FGF23 and in M.L. Olgaard K. Lewin E. New aspects of the kidney in the regulation of fibroblast growth factor 23 (FGF23) and mineral homeostasis.Int J Mol PubMed Scopus Google Y. R. M. et of in patients with Clin PubMed Scopus Google Scholar FGF23 is a of vitamin D metabolism and phosphate A. Mohammadi M. The FGF family: biology, pathophysiology and therapy.Nat Rev Drug Discov. 2009; 8: 235-253https://doi.org/10.1038/nrd2792Crossref PubMed Scopus (1391) Google C. Sabbà C. Moschetta A. Therapeutic potential of the endocrine fibroblast growth factors FGF19, FGF21 and FGF23.Nat Rev Drug Discov. 2016; 15: 51-69https://doi.org/10.1038/nrd.2015.9Crossref PubMed Scopus (283) Google H. M. more than a of phosphate 2010; PubMed Scopus Google M.S. wasting and fibroblast growth Opin 20: PubMed Scopus Google C. Zeitz U. et FGF23 deficiency not glucose or metabolism in mice with a vitamin D PubMed Scopus Google Scholar, and as 2021; PubMed Scopus Google Scholar, R.G. actions of fibroblast growth PubMed Scopus Google Scholar, M. mechanisms of FGF23 Rep. PubMed Scopus Google Scholar, Sitara D. between fibroblast growth factor and inflammation in kidney disease.Curr Opin Nephrol Hypertens. PubMed Scopus Google Scholar, M. et body mass and in patients to elevated fibroblast growth factor J PubMed Scopus Google Scholar protein on the physiological regulation of mineral and and energy metabolism by the endocrine of M.S. The role of klotho in energy Rev 8: PubMed Scopus Google Scholar FGF23 has a with its coreceptor klotho deficiency increases FGF23 and elevated FGF23 klotho deficiency low vitamin J. on chronic kidney disease mineral and bone in Full Text Full Text PDF PubMed Scopus Google Scholar FGF23 levels to as as stage to 3 CKD, to to as CKD to kidney A. Mohammadi M. The FGF family: biology, pathophysiology and therapy.Nat Rev Drug Discov. 2009; 8: 235-253https://doi.org/10.1038/nrd2792Crossref PubMed Scopus (1391) Google and as 2021; PubMed Scopus Google S. Y. 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The FGF family: biology, pathophysiology and therapy.Nat Rev Drug Discov. 2009; 8: 235-253https://doi.org/10.1038/nrd2792Crossref PubMed Scopus (1391) Google C. Sabbà C. Moschetta A. Therapeutic potential of the endocrine fibroblast growth factors FGF19, FGF21 and FGF23.Nat Rev Drug Discov. 2016; 15: 51-69https://doi.org/10.1038/nrd.2015.9Crossref PubMed Scopus (283) Google H. M. more than a of phosphate 2010; PubMed Scopus Google M.S. wasting and fibroblast growth Opin 20: PubMed Scopus Google Scholar with and Sitara D. between fibroblast growth factor and inflammation in kidney disease.Curr Opin Nephrol Hypertens. PubMed Scopus Google B. C. The role of fibroblast growth factor 23 in inflammation and J Mol PubMed Scopus Google Scholar The between and inflammation are and inflammation FGF23 and FGF23 and Sitara D. between fibroblast growth factor and inflammation in kidney disease.Curr Opin Nephrol Hypertens. 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