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The exerkine apelin reverses age-associated sarcopenia

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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Fig. 1: Aged skeletal muscle has a reduced capacity for apelin production.
Fig. 2: Apln and Aplnr deficiency have consequences on muscle aging.
Fig. 3: Chronic apelin supplementation reverses age-associated muscle weakness.
Fig. 4: APLNR-mediated pathways in aged muscle cells.
Fig. 5: Satellite cells are targeted by apelin during muscle regeneration in aged mice.
Fig. 6: Apelin is correlated with beneficial exercise in humans.

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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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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.

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Correspondence to Cedric Dray.

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Vinel, C., Lukjanenko, L., Batut, A. et al. The exerkine apelin reverses age-associated sarcopenia. Nat Med 24, 1360–1371 (2018). https://doi.org/10.1038/s41591-018-0131-6

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