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Title:           Decoding the muscle transcriptome of patients with late-onset Pompe disease reveals markers of disease progression
Subject:         DOI: 10.1093/brain/awae249; Brain, 147, 12, 2024-07-24.; Abstract: 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
Keywords:        glycogen storage disease; mitochondria abnormality; metabolism
Author:          Alexandra Monceau
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     Item: 
      Title: Introduction
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     Item: 
      Title: Materials and methods
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      Children: 
       Item: 
        Title: Muscle samples
        Destination: secawae249-s2.1
       Item: 
        Title: Purification of nuclei from human muscle biopsies
        Destination: secawae249-s2.2
       Item: 
        Title: Single-nucleus RNA sequencing
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       Item: 
        Title: Bioinformatic analysis of single nuclei
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       Item: 
        Title: Enriched signalling pathway analysis
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        Title: Differential gene expression analysis of GeoMX data
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     Item: 
      Title: Results
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        Title: Patients and samples
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       Item: 
        Title: Cell populations identified in the skeletal muscle samples
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       Item: 
        Title: Differences in cell populations between control and Pompe disease samples
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       Item: 
        Title: Muscle samples from Pompe disease patients do not show prominent signs of regeneration
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       Item: 
        Title: Gene expression profile of myofibres reveals differences between Pompe disease and controls
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       Item: 
        Title: Pompe muscle fibres exhibit altered gene expression in metabolic pathways
        Destination: secawae249-s3.6
       Item: 
        Title: Pompe disease muscle fibres display dysregulated autophagy
        Destination: secawae249-s3.7
       Item: 
        Title: Spatial transcriptomics suggest a sequence of biological events
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       Item: 
        Title: Characterization of myofibre gene expression profile reveals changes between Pompe and Pompe + ERT
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      Title: Discussion
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      Title: Conclusion
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      Title: Data availability
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      Title: Funding
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     Item: 
      Title: Competing interests
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     Item: 
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    Title: Decoding the muscle transcriptome of patients with late-onset Pompe disease reveals markers of disease progression
    Author: Alexandra Monceau
    Subject: DOI: 10.1093/brain/awae249; Brain, 147, 12, 2024-07-24.; Abstract: 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
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   Type: CRC32
  Checksum: 636d1ba2167bfb62bd81e2cb7e0c6c1e
   Type: MD5
  Checksum: 6332e6cbe41a72831702117c0cc28ba1f79d3f4a
   Type: SHA-1
  Checksum: 5c2685712a71d522cd2a75508e55b86e31de18aceecda5020bd6681c752e0b68
   Type: SHA-256