Muscle mitochondrial stress adaptation operates independently of endogenous FGF21 action

Molecular Metabolism
Mario OstSusanne Klaus

Abstract

Fibroblast growth factor 21 (FGF21) was recently discovered as stress-induced myokine during mitochondrial disease and proposed as key metabolic mediator of the integrated stress response (ISR) presumably causing systemic metabolic improvements. Curiously, the precise cell-non-autonomous and cell-autonomous relevance of endogenous FGF21 action remained poorly understood. We made use of the established UCP1 transgenic (TG) mouse, a model of metabolic perturbations made by a specific decrease in muscle mitochondrial efficiency through increased respiratory uncoupling and robust metabolic adaptation and muscle ISR-driven FGF21 induction. In a cross of TG with Fgf21-knockout (FGF21(-/-)) mice, we determined the functional role of FGF21 as a muscle stress-induced myokine under low and high fat feeding conditions. Here we uncovered that FGF21 signaling is dispensable for metabolic improvements evoked by compromised mitochondrial function in skeletal muscle. Strikingly, genetic ablation of FGF21 fully counteracted the cell-non-autonomous metabolic remodeling and browning of subcutaneous white adipose tissue (WAT), together with the reduction of circulating triglycerides and cholesterol. Brown adipose tissue activity was similar in all...Continue Reading

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Citations

Feb 24, 2016·Free Radical Biology & Medicine·Mario OstSusanne Klaus
Jul 8, 2016·Adipocyte·Claude ForestPhilippe Noirez
Dec 18, 2016·The Journal of Cell Biology·Hyo Kyun ChungMinho Shong
Aug 22, 2017·Journal of Clinical Medicine·Alireza MorovatJoanna Poulton
Mar 22, 2019·Journal of Cachexia, Sarcopenia and Muscle·Lynette J OostVanina Romanello
Jun 30, 2018·The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences·Maria ConteStefano Salvioli
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May 26, 2020·EMBO Reports·Raz Bar-ZivAndrew Dillin
Sep 10, 2019·Aging·Jiahao DuanChun Yang
Jul 8, 2018·Essays in Biochemistry·Sara Boenzi, Daria Diodato
Feb 23, 2017·Proceedings of the National Academy of Sciences of the United States of America·Ryan M MorrowDouglas C Wallace
Feb 2, 2020·Nature Communications·Susanne KeipertMartin Jastroch
Jan 20, 2021·Cellular and Molecular Life Sciences : CMLS·Susanne KlausMario Ost
Dec 31, 2020·International Journal of Molecular Sciences·Vanina Romanello
Apr 4, 2021·International Journal of Molecular Sciences·Li MengSusanne Klaus
May 3, 2021·Clinical Nutrition : Official Journal of the European Society of Parenteral and Enteral Nutrition·Kun Woo KimKuk Hui Son

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Datasets Mentioned

BETA
GSE71749

Methods Mentioned

BETA
transgenic
X-ray
ELISA
PCR
FACS

Software Mentioned

Stat Graph Prism
GraphPad
EchoMRI
MetaCore

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