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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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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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.
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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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