Both enantiomers of β-aminoisobutyric acid BAIBA regulate Fgf23 via MRGPRD receptor by activating distinct signaling pathways in osteocytes
Eijiro Sakamoto,
Yukiko Kitase,
Alexander J. Fitt,
Zewu Zhu,
Kamal Awad,
Marco Brotto,
Kenneth E. White,
Steven S. Welc,
Clemens Bergwitz,
Lynda F. Bonewald
Affiliations
Eijiro Sakamoto
Department of Anatomy, Cell Biology, & Physiology, School of Medicine, Indiana University, Indianapolis, IN 46202, USA; Indiana Center for Musculoskeletal Health, School of Medicine, Indiana University, Indianapolis, IN 46202, USA
Yukiko Kitase
Department of Anatomy, Cell Biology, & Physiology, School of Medicine, Indiana University, Indianapolis, IN 46202, USA; Indiana Center for Musculoskeletal Health, School of Medicine, Indiana University, Indianapolis, IN 46202, USA; Corresponding author
Alexander J. Fitt
Department of Anatomy, Cell Biology, & Physiology, School of Medicine, Indiana University, Indianapolis, IN 46202, USA
Zewu Zhu
Section of Endocrinology and Metabolism, Yale School of Medicine, New Haven, CT 06519, USA
Kamal Awad
Bone-Muscle Research Center, College of Nursing & Health Innovation, University of Texas-Arlington, Arlington, TX 76019, USA
Marco Brotto
Bone-Muscle Research Center, College of Nursing & Health Innovation, University of Texas-Arlington, Arlington, TX 76019, USA
Kenneth E. White
Indiana Center for Musculoskeletal Health, School of Medicine, Indiana University, Indianapolis, IN 46202, USA; Department of Molecular and Medical Genetics, School of Medicine, Indiana University, Indianapolis, IN 46202, USA
Steven S. Welc
Department of Anatomy, Cell Biology, & Physiology, School of Medicine, Indiana University, Indianapolis, IN 46202, USA; Indiana Center for Musculoskeletal Health, School of Medicine, Indiana University, Indianapolis, IN 46202, USA
Clemens Bergwitz
Section of Endocrinology and Metabolism, Yale School of Medicine, New Haven, CT 06519, USA
Lynda F. Bonewald
Department of Anatomy, Cell Biology, & Physiology, School of Medicine, Indiana University, Indianapolis, IN 46202, USA; Indiana Center for Musculoskeletal Health, School of Medicine, Indiana University, Indianapolis, IN 46202, USA; Department of Orthopaedic Surgery, School of Medicine, Indiana University, Indianapolis, IN 46202, USA; Corresponding author
Summary: With exercise, muscle and bone produce factors with beneficial effects on brain, fat, and other organs. Exercise in mice increased fibroblast growth factor 23 (FGF23), urine phosphate, and the muscle metabolite L-β-aminoisobutyric acid (L-BAIBA), suggesting that L-BAIBA may play a role in phosphate metabolism. Here, we show that L-BAIBA increases in serum with exercise and elevates Fgf23 in osteocytes. The D enantiomer, described to be elevated with exercise in humans, can also induce Fgf23 but through a delayed, indirect process via sclerostin. The two enantiomers both signal through the same receptor, Mas-related G-protein-coupled receptor type D, but activate distinct signaling pathways; L-BAIBA increases Fgf23 through Gαs/cAMP/PKA/CBP/β-catenin and Gαq/PKC/CREB, whereas D-BAIBA increases Fgf23 indirectly through sclerostin via Gαi/NF-κB. In vivo, both enantiomers increased Fgf23 in bone in parallel with elevated urinary phosphate excretion. Thus, exercise-induced increases in BAIBA and FGF23 work together to maintain phosphate homeostasis.
