دورية أكاديمية
FSHD muscle shows perturbation in fibroadipogenic progenitor cells, mitochondrial function and alternative splicing independently of inflammation.
| العنوان: | FSHD muscle shows perturbation in fibroadipogenic progenitor cells, mitochondrial function and alternative splicing independently of inflammation. |
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| المؤلفون: | Engquist EN; Randall Centre for Cell and Molecular Biophysics, King's College London, New Hunt's House, Guy's Campus, London SE1 1UL, United Kingdom., Greco A; Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, 6525 GA, The Netherlands.; Department of Internal Medicine, Radboud Institute of Molecular Life Sciences (RIMLS) and Radboud Center of Infectious Diseases (RCI), Radboud University Medical Center, Geert Grooteplein Zuid 10, Nijmegen 6525 GA, The Netherlands., Joosten LAB; Department of Internal Medicine, Radboud Institute of Molecular Life Sciences (RIMLS) and Radboud Center of Infectious Diseases (RCI), Radboud University Medical Center, Geert Grooteplein Zuid 10, Nijmegen 6525 GA, The Netherlands.; Department of Medical Genetics, Iuliu Hatieganu University of Medicine and Pharmacy, 400012, Cluj-Napoca, Romania., van Engelen BGM; Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, 6525 GA, The Netherlands., Zammit PS; Randall Centre for Cell and Molecular Biophysics, King's College London, New Hunt's House, Guy's Campus, London SE1 1UL, United Kingdom., Banerji CRS; Randall Centre for Cell and Molecular Biophysics, King's College London, New Hunt's House, Guy's Campus, London SE1 1UL, United Kingdom.; The Alan Turing Institute, The British Library, 96 Euston Road, London NW1 2DB, United Kingdom. |
| المصدر: | Human molecular genetics [Hum Mol Genet] 2024 Jan 07; Vol. 33 (2), pp. 182-197. |
| نوع المنشور: | Meta-Analysis; Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: IRL Press at Oxford University Press Country of Publication: England NLM ID: 9208958 Publication Model: Print Cited Medium: Internet ISSN: 1460-2083 (Electronic) Linking ISSN: 09646906 NLM ISO Abbreviation: Hum Mol Genet Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Oxford, England ; New York : IRL Press at Oxford University Press, c1992- |
| مواضيع طبية MeSH: | Muscular Dystrophy, Facioscapulohumeral*/pathology, Humans ; Alternative Splicing/genetics ; Inflammation/pathology ; Mitochondria/metabolism ; Muscle, Skeletal/metabolism ; Stem Cells/metabolism |
| مستخلص: | Facioscapulohumeral muscular dystrophy (FSHD) is a prevalent, incurable myopathy. FSHD is highly heterogeneous, with patients following a variety of clinical trajectories, complicating clinical trials. Skeletal muscle in FSHD undergoes fibrosis and fatty replacement that can be accelerated by inflammation, adding to heterogeneity. Well controlled molecular studies are thus essential to both categorize FSHD patients into distinct subtypes and understand pathomechanisms. Here, we further analyzed RNA-sequencing data from 24 FSHD patients, each of whom donated a biopsy from both a non-inflamed (TIRM-) and inflamed (TIRM+) muscle, and 15 FSHD patients who donated peripheral blood mononucleated cells (PBMCs), alongside non-affected control individuals. Differential gene expression analysis identified suppression of mitochondrial biogenesis and up-regulation of fibroadipogenic progenitor (FAP) gene expression in FSHD muscle, which was particularly marked on inflamed samples. PBMCs demonstrated suppression of antigen presentation in FSHD. Gene expression deconvolution revealed FAP expansion as a consistent feature of FSHD muscle, via meta-analysis of 7 independent transcriptomic datasets. Clustering of muscle biopsies separated patients in an unbiased manner into clinically mild and severe subtypes, independently of known disease modifiers (age, sex, D4Z4 repeat length). Lastly, the first genome-wide analysis of alternative splicing in FSHD muscle revealed perturbation of autophagy, BMP2 and HMGB1 signalling. Overall, our findings reveal molecular subtypes of FSHD with clinical relevance and identify novel pathomechanisms for this highly heterogeneous condition. (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.) |
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| معلومات مُعتمدة: | United Kingdom WT_ Wellcome Trust; WT 222352/Z/21/Z United Kingdom WT_ Wellcome Trust; MR/P023215/1 United Kingdom MRC_ Medical Research Council |
| فهرسة مساهمة: | Keywords: alternative splicing; facioscapulohumeral muscular dystrophy (FSHD); fibroadipogenic progenitor cells (FAPs); mitochondrial function; transcriptomics |
| المشرفين على المادة: | EC 3.4.21.- (fibroblast activation protein alpha) |
| تواريخ الأحداث: | Date Created: 20231019 Date Completed: 20240111 Latest Revision: 20240210 |
| رمز التحديث: | 20240210 |
| مُعرف محوري في PubMed: | PMC10772042 |
| DOI: | 10.1093/hmg/ddad175 |
| PMID: | 37856562 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 1460-2083 |
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| DOI: | 10.1093/hmg/ddad175 |