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Fibroblast growth factor 19 regulates skeletal muscle mass and ameliorates muscle wasting in mice

Nature Medicine volume 23, pages 990–996 (2017)Cite this article

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Abstract

The endocrine-derived hormone fibroblast growth factor (FGF) 19 has recently emerged as a potential target for treating metabolic disease1. Given that skeletal muscle is a key metabolic organ, we explored the role of FGF19 in that tissue. Here we report a novel function of FGF19 in regulating skeletal muscle mass through enlargement of muscle fiber size, and in protecting muscle from atrophy. Treatment with FGF19 causes skeletal muscle hypertrophy in mice, while physiological and pharmacological doses of FGF19 substantially increase the size of human myotubes in vitro. These effects were not elicited by FGF21, a closely related endocrine FGF member. Both in vitro and in vivo, FGF19 stimulates the phosphorylation of the extracellular-signal-regulated protein kinase 1/2 (ERK1/2) and the ribosomal protein S6 kinase (S6K1), an mTOR-dependent master regulator of muscle cell growth. Moreover, mice with a skeletal-muscle-specific genetic deficiency of β-Klotho (KLB), an obligate co-receptor for FGF15/19 (refs. 2,3), were unresponsive to the hypertrophic effect of FGF19. Finally, in mice, FGF19 ameliorates skeletal muscle atrophy induced by glucocorticoid treatment or obesity, as well as sarcopenia. Taken together, these findings provide evidence that the enterokine FGF19 is a novel factor in the regulation of skeletal muscle mass, and that it has therapeutic potential for the treatment of muscle wasting.

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Figure 1: FGF19 treatment induces skeletal muscle hypertrophy in vivo.
Figure 2: Effect of FGF19 on human myotube area and characterization of the FGF19 signaling pathway in skeletal muscle.
Figure 3: β-Klotho is essential for FGF19-induced muscle hypertrophy.
Figure 4: The impact of FGF19 on skeletal muscle in glucocorticoid-treated mice, aged mice and a genetic mouse model of obesity.

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Acknowledgements

We thank D.J. Mangelsdorf and S.A. Kliewer (University of Texas Southwestern Medical Center, Dallas, Texas, USA) for providing the Klb+/−, Klb−/− and Klbfl/fl mice and J. Melki (Université Paris Sud, Paris, France) for providing the HSA-Cre mice. We thank the Plateau de Biologie Expérimentale de la Souris (Ecole Normale Supérieure, Lyon, France) for excellent animal care and breeding. This work was supported by the Research Council of Norway (projects #230394 and #228135) and from INSERM and INRA research funds. B.B. is supported by a grant from the Environmental Exposures and Health Outcomes programme from the Research Council of Norway. J. Ruzzin is supported by the FRIPRO Young Research Talents programme from the Research Council of Norway.

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Author notes

  1. Bérengère Benoit, Emmanuelle Meugnier and Martina Castelli: These authors contributed equally to this work.

  2. Hubert Vidal and Jérôme Ruzzin: These authors jointly directed this work.

Authors and Affiliations

  1. Department of Biology, University of Bergen, Bergen, Norway

    Bérengère Benoit, Martina Castelli & Jérôme Ruzzin

  2. Univ-Lyon, CarMeN Laboratory, INSERM 1060, INRA 1397, Université Claude Bernard Lyon1,

    Emmanuelle Meugnier, Stéphanie Chanon, Aurélie Vieille-Marchiset, Christine Durand, Nadia Bendridi, Sandra Pesenti, Pierre-Axel Monternier, Jennifer Rieusset, Etienne Lefai & Hubert Vidal

  3. , INSA Lyon, Oullins, France

    Emmanuelle Meugnier, Stéphanie Chanon, Aurélie Vieille-Marchiset, Christine Durand, Nadia Bendridi, Sandra Pesenti, Pierre-Axel Monternier, Jennifer Rieusset, Etienne Lefai & Hubert Vidal

  4. Univ-Lyon, Laboratoire Interuniversitaire de Biologie de la Motricité, EA7424, Université Jean Monnet, Saint Etienne, France

    Anne-Cécile Durieux & Damien Freyssenet

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  1. Bérengère Benoit
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Contributions

D.F., E.L., H.V. and J. Ruzzin conceived and designed the study. B.B., E.M., M.C., S.C., A.V.-M., C.D., N.B., P.-A.M., S.P., A.-C.D., J. Rieusset and J. Ruzzin performed the experiments. B.B., H.V. and J. Ruzzin wrote the manuscript, with contributions from all the other authors.

Corresponding author

Correspondence to Jérôme Ruzzin.

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Competing interests

A patent covering the hypertrophic effect of FGF15/19 in muscle has been filed.

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Benoit, B., Meugnier, E., Castelli, M. et al. Fibroblast growth factor 19 regulates skeletal muscle mass and ameliorates muscle wasting in mice. Nat Med 23, 990–996 (2017). https://doi.org/10.1038/nm.4363

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