Cholesterol metabolism is a potential therapeutic target in Duchenne muscular dystrophy
Autor: | Guillaume Corre, Laurence Suel, David Israeli, Ai Vu Hong, Laurent Servais, Thomas Voit, Isabelle Richard, Fatima Amor, Mathilde Sanson, Stephanie Blaie |
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Přispěvatelé: | Généthon, Approches génétiques intégrées et nouvelles thérapies pour les maladies rares (INTEGRARE), Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Généthon, University of Oxford [Oxford], University College of London [London] (UCL), University of Oxford, Richard, Isabelle |
Jazyk: | angličtina |
Rok vydání: | 2021 |
Předmět: |
0301 basic medicine
Male mdx mouse Simvastatin Duchenne muscular dystrophy Diseases of the musculoskeletal system Extracellular matrix Mice 0302 clinical medicine Glucocorticoid Myocyte Orthopedics and Sports Medicine DLK1‐DIO3 [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism 0303 health sciences Host gene [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism 3. Good health Cell biology Cholesterol 030220 oncology & carcinogenesis [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry Molecular Biology/Genomics [q-bio.GN] Original Article Mevalonate pathway musculoskeletal diseases SREBP-2 congenital hereditary and neonatal diseases and abnormalities Biology Biological interpretation of miRNA dysregulation 03 medical and health sciences Physiology (medical) [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry Molecular Biology/Genomics [q-bio.GN] medicine Animals Humans SREBP‐1 SREBP‐2 DLK1-DIO3 Muscle Skeletal 030304 developmental biology SREBP-1 Sarcolemma business.industry QM1-695 Lipid metabolism Original Articles medicine.disease Actin cytoskeleton Sterol regulatory element-binding protein Muscular Dystrophy Duchenne 030104 developmental biology RC925-935 Human anatomy Mice Inbred mdx business Homeostasis 030217 neurology & neurosurgery |
Zdroj: | Journal of Cachexia, Sarcopenia and Muscle Journal of Cachexia, Sarcopenia and Muscle, Wiley Open Access/Springer Verlag, 2021, 12 (3), pp.677-693. ⟨10.1002/jcsm.12708⟩ Journal of Cachexia, Sarcopenia and Muscle, 2021, 12 (3), pp.677-693. ⟨10.1002/jcsm.12708⟩ Journal of Cachexia, Sarcopenia and Muscle, Vol 12, Iss 3, Pp 677-693 (2021) |
ISSN: | 2190-5991 2190-6009 |
DOI: | 10.1002/jcsm.12708⟩ |
Popis: | BackgroundDuchenne Muscular Dystrophy (DMD) is a lethal muscle disease detected in approximately 1:5000 male births. DMD is caused by mutations in the DMD gene, encoding a critical protein that link the cytoskeleton and the extracellular matrix in skeletal and cardiac muscles. The primary consequence of the disrupted link between the extracellular matrix and the myofiber actin cytoskeleton is thought to involve sarcolemma destabilization, perturbation of Ca+2 homeostasis, activation of proteases, mitochondrial damage and tissue degeneration. A recently emphasized secondary aspect of the dystrophic process is a progressive metabolic change of the dystrophic tissue; however, the mechanism and nature of the metabolic dysregulation is yet poorly understood. In this study, we characterized a molecular mechanism of metabolic perturbation in DMD.MethodsWe sequenced plasma miRNA in a DMD cohort, comprising of 54 DMD patients treated or not by glucocorticoid, compared to 27 healthy controls, in three age groups. We developed an original approach for the biological interpretation of miRNA dysregulation, and produced a novel hypothesis concerning metabolic perturbation in DMD. We then used the mdx mouse model for DMD for the investigation of this hypothesis.ResultsWe identified 96 dysregulated miRNAs, of which 74 were up- and 22 down-regulated in DMD. We confirmed the dysregulation in DMD of Dystro-miRs, Cardio-miRs and a large number of the DLK1-DIO3 miRNAs. We also identified numerous dysregulated miRNAs, yet unreported in DMD. Bioinformatics analysis of both target and host genes for dysregulated miRNAs predicted that lipid metabolism might be a critical metabolic perturbation in DMD. Investigation of skeletal muscles of the mdx mouse uncovered dysregulation of transcription factors of cholesterol and fatty acid metabolism (SREBP1 and SREBP2), perturbation of the mevalonate pathway, and accumulation of cholesterol. Elevated cholesterol level was also found in muscle biopsies of DMD patients. Treatment of mdx mice with Simvastatin, a cholesterol-reducing agent, normalized these perturbations and partially restored the dystrophic parameters.ConclusionThis investigation supports that cholesterol metabolism and the mevalonate pathway are potential therapeutic targets in DMD. |
Databáze: | OpenAIRE |
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