RT Journal Article
SR Electronic
T1 FGF21-FGFR4 signaling in cardiac myocytes promotes concentric cardiac hypertrophy in mouse models of diabetes
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.09.16.460632
DO 10.1101/2021.09.16.460632
A1 Christopher Yanucil
A1 Dominik Kentrup
A1 Xueyi Li
A1 Alexander Grabner
A1 Karla Schramm
A1 Eliana C. Martinez
A1 Jinliang Li
A1 Isaac Campos
A1 Brian Czaya
A1 Kylie Heitman
A1 David Westbrook
A1 Adam Wende
A1 Alexis Sloan
A1 Johanna M. Roche
A1 Alessia Fornoni
A1 Michael S. Kapiloff
A1 Christian Faul
YR 2021
UL http://biorxiv.org/content/early/2021/09/16/2021.09.16.460632.abstract
AB Fibroblast growth factor (FGF) 21, a hormone that increases insulin sensitivity, has shown promise as a therapeutic agent to improve metabolic dysregulation. Here we report that FGF21 directly targets cardiac myocytes by binding β-klotho and FGF receptor (FGFR) 4. In combination with high glucose, FGF21 induces cardiac myocyte growth in width mediated by extracellular signal-regulated kinase 1/2 (ERK1/2) signaling. While short-term FGF21 elevation can be cardio-protective, we find that in type 2 diabetes (T2D) in mice, where serum FGF21 levels are elevated, FGFR4 activation induces concentric cardiac hypertrophy. As T2D patients are at risk for heart failure with preserved ejection fraction (HFpEF), we propose that induction of concentric hypertrophy by elevated FGF21-FGFR4 signaling constitutes a novel mechanism promoting T2D-associated HFpEF and that FGFR4 blockade might serve as a cardio-protective therapy in T2D. In addition, potential adverse cardiac effects of FGF21 mimetics currently in clinical trials should be investigated.Competing Interest StatementC.F. and D.K. have served as consultants for Bayer, and C.F. also for Calico Labs. C.Y. and C.F. are inventors on two pending patents (PCT/US2019/049211; PCT/US19/49161) and they are co-founders of a startup biotech company (Alpha Young LLC). C.F. is a founder and the CSO of Alpha Young LLC. C.F. has a patent on FGFR inhibition (European Patent No. 2723391). A.F. is vice-president of L&F Health LLC and the scientist co-founder and a shareholder of ZyVersa Therapeutics Inc and River 3 Renal Corp.