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Lookup NU author(s): Dr Alexandra Monceau, Esther Fernández-SimónORCiD, Dr Elisa Villalobos VillegasORCiD, James Clark, Panos Katsikis, Priyanka Mehra, Zoe Laidler, Dr Amy VincentORCiD, Professor Giorgio TascaORCiD, Professor Chiara Marini Bettolo, Professor Michela GuglieriORCiD, Professor Volker StraubORCiD
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC 4.0).
© 2024 The Author(s). Late-onset Pompe disease (LOPD) is a rare genetic disorder caused by the deficiency of acid alpha-glucosidase leading to progressive cellular dysfunction owing to the accumulation of glycogen in the lysosome. The mechanism of relentless muscle damage (a classic manifestation of the disease) has been studied extensively by analysing the whole-muscle tissue; however, little, if anything, is known about transcriptional heterogeneity among nuclei within the multinucleated skeletal muscle cells. This is the first report of application of single-nucleus RNA sequencing to uncover changes in the gene expression profile in muscle biopsies from eight patients with LOPD and four muscle samples from age- and sex-matched healthy controls. We matched these changes with histological findings using GeoMx spatial transcriptomics to compare the transcriptome of control myofibres from healthy individuals with non-vacuolated (histologically unaffected) and vacuolated (histologically affected) myofibres of LODP patients. We observed an increase in the proportion of slow and regenerative muscle fibres and macrophages in LOPD muscles. The expression of the genes involved in glycolysis was reduced, whereas the expression of the genes involved in the metabolism of lipids and amino acids was increased in non-vacuolated fibres, indicating early metabolic abnormalities. Additionally, we detected upregulation of autophagy genes and downregulation of the genes involved in ribosomal and mitochondrial function leading to defective oxidative phosphorylation. Upregulation of genes associated with inflammation, apoptosis and muscle regeneration was observed only in vacuolated fibres. Notably, enzyme replacement therapy (the only available therapy for the disease) showed a tendency to restore dysregulated metabolism, particularly within slow fibres. A combination of single-nucleus RNA sequencing and spatial transcriptomics revealed the landscape of the normal and diseased muscle and highlighted the early abnormalities associated with disease progression. Thus, the application of these two new cutting-edge technologies provided insight into the molecular pathophysiology of muscle damage in LOPD and identified potential avenues for therapeutic intervention.
Author(s): Monceau A, Nath RG, Suarez-Calvet X, Musumeci O, Toscano A, Kierdaszuk B, Kostera-Pruszczyk A, Dominguez-Gonzalez C, Hernandez-Lain A, Paradas C, Rivas E, Papadimas G, Papadopoulos C, Chrysanthou-Piterou M, Gallardo E, Olivé M, Lilleker J, Roberts ME, Marchese D, Lunazzi G, Heyn H, Fernandez-Simon E, Villalobos E, Clark J, Katsikis P, Collins C, Mehra P, Laidler Z, Vincent A, Tasca G, Marini-Bettolo C, Guglieri M, Straub V, Raben N, Diaz-Manera J
Publication type: Article
Publication status: Published
Journal: Brain
Year: 2024
Volume: 147
Issue: 12
Pages: 4213-4226
Print publication date: 01/12/2024
Online publication date: 24/07/2024
Acceptance date: 30/06/2024
Date deposited: 09/01/2025
ISSN (print): 0006-8950
ISSN (electronic): 1460-2156
Publisher: Oxford University Press
URL: https://doi.org/10.1093/brain/awae249
DOI: 10.1093/brain/awae249
Data Access Statement: All the raw data and processed data are available on request to the corresponding author.
PubMed id: 39045638
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