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Sphingolipids accumulate in aged muscle, and their reduction counteracts sarcopenia

Nature Aging volume 2, pages 1159–1175 (2022)Cite this article

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Abstract

Age-related muscle dysfunction and sarcopenia are major causes of physical incapacitation in older adults and currently lack viable treatment strategies. Here we find that sphingolipids accumulate in mouse skeletal muscle upon aging and that both genetic and pharmacological inhibition of sphingolipid synthesis prevent age-related decline in muscle mass while enhancing strength and exercise capacity. Inhibition of sphingolipid synthesis confers increased myogenic potential and promotes protein synthesis. Within the sphingolipid pathway, we show that accumulation of dihydroceramides is the culprit disturbing myofibrillar homeostasis. The relevance of sphingolipid pathways in human aging is demonstrated in two cohorts, the UK Biobank and Helsinki Birth Cohort Study in which gene expression-reducing variants of SPTLC1 and DEGS1 are associated with improved and reduced fitness of older individuals, respectively. These findings identify sphingolipid synthesis inhibition as an attractive therapeutic strategy for age-related sarcopenia and co-occurring pathologies.

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Fig. 1: Sphingolipid de novo synthesis is activated upon aging in skeletal muscle.
Fig. 2: Inactivation of sphingolipid de novo synthesis increases muscle mass and improves muscle function.
Fig. 3: Inhibition of sphingolipid de novo synthesis transcriptionally upregulates myogenic differentiation.
Fig. 4: Skeletal muscle-specific Sptlc1 inhibition improves muscle morphology and function in aged mice.
Fig. 5: Sphingolipid depletion activates myogenic differentiation cell autonomously and promotes protein synthesis.
Fig. 6: Sphingolipid depletion cell autonomously activates muscle differentiation in progenitor cells.
Fig. 7: Dihydroceramide accumulation blunts the myogenic response to Sptlc1 deficiency, and genetic variation in SPTLC1 and DEGS1 is associated with age-related fitness in humans.

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Data availability

RNA sequencing data are deposited in the GEO repository with the ID GSE213110. Experiments are depicted as single data points to enhance transparency. Experimental data are available upon reasonable request from the corresponding authors. Human clinical data from the HBCS cannot be shared due to data privacy. UKBB data are available from the public repository. Source data are provided with this paper.

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Acknowledgements

We wish to thank the staff of the Ecole Polytechnique Federale de Lausanne (EPFL) histology, flow cytometry and animal facilities for technical assistance. J. Tuhkanen is thanked for data management with the HBCS. We also wish to acknowledge T. Teav (from the Metabolomics Platform at UNIL) for his help with sphingolipid measurement. The work in the laboratory of J.A. was supported by grants from the EPFL, the European Research Council (ERC-AdG-787702), the Swiss National Science Foundation (SNSF 31003A_179435), the Fondation Suisse de Recherche sur les Maladies Musculaires (FSRMM) and the Fondation Marcel Levaillant (190917). We thank all study participants as well as everybody involved in the HBCS. The work has been supported by the Academy of Finland, the Finnish Diabetes Research Society, the Folkhälsan Research Foundation, the Novo Nordisk Foundation, Finska Läkaresällskapet, the Finnish Foundation for Cardiovascular Research, the Juho Vainio Foundation, the Signe and Ane Gyllenberg Foundation, the University of Helsinki, the Sigrid Juselius Foundation, the Ministry of Education, the Ahokas Foundation, the Emil Aaltonen Foundation, the Paavo Nurmi Foundation, the Orion Foundation and a Scottish Senior Clinical Fellowship (SCD/09). We would also like to acknowledge the Genetics Core of the Wellcome Trust Clinical Research Facility (Edinburgh, UK) who ran the 450k array for the HBCS samples. P.-P.L. was a recipient of a Sigrid Juselius Fellowship. This research has been conducted using the UKBB resource.

Author information

Author notes

  1. These authors contributed equally: Pirkka-Pekka Laurila, Martin Wohlwend.

Authors and Affiliations

  1. Laboratory of Integrative Systems Physiology, École polytechnique fédérale de Lausanne (EPFL), Lausanne, Switzerland

    Pirkka-Pekka Laurila, Martin Wohlwend, Tanes Imamura de Lima, Peiling Luan, Sébastien Herzig, Barbara Crisol, Maroun Bou-Sleiman, Qi Wang, Davide D’Amico & Johan Auwerx

  2. Institute of Sport Sciences and Department of Biomedical Sciences, University of Lausanne, Lausanne, Switzerland

    Nadège Zanou & Nicolas Place

  3. Swiss Institute of Bioinformatics, Lausanne, Switzerland

    Eleonora Porcu & Zoltan Kutalik

  4. Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland

    Eleonora Porcu

  5. Metabolomics Platform, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland

    Hector Gallart-Ayala & Julijana Ivanisevic

  6. Molecular and Cellular Biology Laboratory, The Salk Institute for Biological Studies, La Jolla, CA, USA

    Michal K. Handzlik & Christian M. Metallo

  7. Intonation Research Laboratories, Secunderabad, India

    Suresh Jain

  8. Chronic Disease Prevention Unit, National Institute for Health and Welfare, Helsinki, Finland

    Minna Salonen

  9. University Center for Primary Care and Public Health, University of Lausanne, Lausanne, Switzerland

    Zoltan Kutalik

  10. Institute of Molecular Biosciences, University of Graz, Graz, Austria

    Thomas O. Eichmann

  11. Center for Explorative Lipidomics, BioTechMed-Graz, Graz, Austria

    Thomas O. Eichmann

  12. Department of Psychology and Logopedics, University of Helsinki, Helsinki, Finland

    Jari Lahti

  13. Turku Institute for Advanced Studies, University of Turku, Turku, Finland

    Jari Lahti

  14. Department of General Practice and Primary Health Care, University of Helsinki and Helsinki University Hospital, University of Helsinki, Helsinki, Finland

    Johan G. Eriksson

  15. Folkhälsan Research Center, University of Helsinki, Helsinki, Finland

    Johan G. Eriksson

  16. Department of Obstetrics and Gynecology, National University Singapore, Yong Loo Lin School of Medicine, Singapore, Singapore

    Johan G. Eriksson

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Contributions

The study was conceived and designed by P.-P.L. and J.A. Human and mouse bioinformatics analyses were performed by P.P.L. Mouse phenotyping was carried out by P.-P.L. and N.Z. RNA sequencing was analyzed by M.B.-S. and P.-P.L. In vitro work was performed by M.W., T.I.L., S.H., P.-P.L. and D.D.A. H.G.-A., T.O.E., M.K.H., and J.I. performed sphingolipid measurements. Histological analyses, ex vivo measurements and MuSC extractions and injections were performed by P.L. Genetic analyses were performed by P.-P.L., E.P. and J.L. Human data were collected by M.S. and J.G.E. P.-P.L. and J.A. wrote the manuscript, and all authors gave critical comments on it. Z.K., N.P., C.M. and J.A. supervised the work.

Corresponding authors

Correspondence to Pirkka-Pekka Laurila or Johan Auwerx.

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Competing interests

P.-P.L. and J.A. are inventors on a provisional patent application from the EPFL related to the role of sphingolipids on muscle function. The remaining authors declare no competing interests.

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Nature Aging thanks Yusuf Hannun, Joris Deelen, and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Unprocessed western blots for Supplementary Fig. 7.

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Laurila, PP., Wohlwend, M., Imamura de Lima, T. et al. Sphingolipids accumulate in aged muscle, and their reduction counteracts sarcopenia. Nat Aging 2, 1159–1175 (2022). https://doi.org/10.1038/s43587-022-00309-6

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