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
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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