Abstract

Sarcopenia, the degenerative loss of skeletal muscle mass, quality and strength, lacks early diagnostic tools and new therapeutic strategies to prevent the frailty-to-disability transition often responsible for the medical institutionalization of elderly individuals. Herein we report that production of the endogenous peptide apelin, induced by muscle contraction, is reduced in an age-dependent manner in humans and rodents and is positively associated with the beneficial effects of exercise in older persons. Mice deficient in either apelin or its receptor (APLNR) presented dramatic alterations in muscle function with increasing age. Various strategies that restored apelin signaling during aging further demonstrated that this peptide considerably enhanced muscle function by triggering mitochondriogenesis, autophagy and anti-inflammatory pathways in myofibers as well as enhancing the regenerative capacity by targeting muscle stem cells. Taken together, these findings revealed positive regulatory feedback between physical activity, apelin and muscle function and identified apelin both as a tool for diagnosis of early sarcopenia and as the target of an innovative pharmacological strategy to prevent age-associated muscle weakness and restore physical autonomy.

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Acknowledgements

We thank V. Minville, I. Castan-Laurell, A. Yart, B. Masri, and L. Casteilla for their fruitful discussions. We also specially thank all of the personnel of the ANEXPLO animal facility (Toulouse, France) and transcriptomic GeTQ plateform (Toulouse, France); J. Rouquette, head of the ITAV Imaging Service (Centre Pierre Potier, Toulouse, France); Federico S. and the NIHS flow cytometry facility (Lausanne, Switzerland). We thank J. Iacovani and J. Christensen for corrections to the article and M. Rossell for technical assistance. Mice deficient for AMPK activity (DN-AMPK) in skeletal muscles were kindly provided by the laboratory of M. J. Birnbaum (University of Pennsylvania Medical School, Philadelphia, USA). This work has been funded by INSERM (Institut National de la Santé et de la Recherche Médicale), the Région Occitanie and the Fondation de la Recherche Médicale (FRM). This project was supported in part by European funds (Fonds Européens de Développement Régional, FEDER), Toulouse Métropole, and the French Ministry of Research through the Investissement d’Avenir Infrastructures Nationales en Biologie et Santé program (ProFI, Proteomics French Infrastructure project, ANR-10-INBS-08).

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Author notes

  1. These authors jointly directed this work: Philippe Valet, Cedric Dray.

Affiliations

  1. Institut des Maladies Métaboliques et Cardiovasculaires, INSERM U1048, Université de Toulouse, Université Paul Sabatier, Toulouse, France

    • Claire Vinel
    • , Aurelie Batut
    • , Simon Deleruyelle
    • , Jean-Philippe Pradère
    • , Sophie Le Gonidec
    • , Alizée Dortignac
    • , Nancy Geoffre
    • , Ophelie Pereira
    • , Etienne Mouisel
    • , Fabien Pillard
    • , Philippe Valet
    •  & Cedric Dray
  2. Aging Department, Nestlé Institute of Health Sciences SA, Ecole Polytechnique Fédérale de Lausanne Innovation Park, Lausanne, Switzerland

    • Laura Lukjanenko
    • , Sonia Karaz
    • , Umji Lee
    •  & Jerome N. Feige
  3. Institut de Pharmacologie et de Biologie Structurale–CNRS, Université de Toulouse, Université Paul Sabatier, Toulouse, France

    • Mylène Camus
    • , Karima Chaoui
    •  & Odile Burlet-Schiltz
  4. Institut de Myologie, Université Pierre et Marie Curie, Paris 6 UM76, Univ. Paris 6/U974, UMR7215, CNRS, Pitié-Salpétrière–INSERM, UMRS 974, Paris, France

    • Anne Bigot
    •  & Vincent Mouly
  5. Institut des Technologies Avancées en Science du Vivant–USR3505 Centre Pierre Potier, Toulouse, France

    • Mathieu Vigneau
  6. Université de Montpellier, Institut National de la Recherche Agronomique, UMR866 Dynamique Musculaire et Métabolisme, Montpellier, France

    • Allan F. Pagano
    •  & Angèle Chopard
  7. Gérontopole Toulouse-Purpan UMR 1027, Toulouse, France

    • Sophie Guyonnet
    • , Matteo Cesari
    •  & Bruno Vellas
  8. Institute on Aging, College of Medicine, University of Florida, Gainesville, FL, USA

    • Marco Pahor

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Contributions

C.D. and P.V. conceived the study. C.V., S.L.G., A.D., O.P. and S.D. performed all animal experiments. C.V., L.L., S.K., U.L. and J.F.N. designed, performed and analyzed the regeneration experiments. C.D., C.V. and J.-P.P. performed all the western blots. C.V., A.D., O.P. and N.G. performed all the transcriptomics. V.M. and A.B. provided human cells. A.B. performed all the culture cell experiments. B.V., M.C., M.P., F.P. and S.G. were involved in human samples collection and analysis. A.C. and A.F.P. performed the hindlimb unloading experiments. M.C., K.C. and O.S. designed and performed the HPLC experiments. M.V. analyzed muscle fiber composition. E.M. participated in performing the specific muscle contraction tests. C.D. supervised the design and execution of the study, interpreted the results and wrote the manuscript.

Competing interests

The authors declare no competing interests.

Corresponding author

Correspondence to Cedric Dray.

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https://doi.org/10.1038/s41591-018-0131-6

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