Cholesterol metabolism is a potential therapeutic target in Duchenne muscular dystrophy
Abstract Background Duchenne 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 links the cytoskeleton and the extracellular matrix in skeletal and cardiac muscles. The primary...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2021-06-01
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| Series: | Journal of Cachexia, Sarcopenia and Muscle |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/jcsm.12708 |
| _version_ | 1797203134481694720 |
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| author | Fatima Amor Ai Vu Hong Guillaume Corre Mathilde Sanson Laurence Suel Stephanie Blaie Laurent Servais Thomas Voit Isabelle Richard David Israeli |
| author_facet | Fatima Amor Ai Vu Hong Guillaume Corre Mathilde Sanson Laurence Suel Stephanie Blaie Laurent Servais Thomas Voit Isabelle Richard David Israeli |
| author_sort | Fatima Amor |
| collection | DOAJ |
| description | Abstract Background Duchenne 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 links the cytoskeleton and the extracellular matrix in skeletal and cardiac muscles. The primary consequence of the disrupted link between the extracellular matrix and the myofibre actin cytoskeleton is thought to involve sarcolemma destabilization, perturbation of Ca2+ 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 are yet poorly understood. In this study, we characterized a molecular mechanism of metabolic perturbation in DMD. Methods We sequenced plasma miRNA in a DMD cohort, comprising 54 DMD patients treated or not by glucocorticoid, compared with 27 healthy controls, in three groups of the ages of 4–8, 8–12, and 12–20 years. We developed an original approach for the biological interpretation of miRNA dysregulation and produced a novel hypothesis concerning metabolic perturbation in DMD. We used the mdx mouse model for DMD for the investigation of this hypothesis. Results We identified 96 dysregulated miRNAs (adjusted P‐value <0.1), of which 74 were up‐regulated and 22 were 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 (SREBP‐1 and SREBP‐2), perturbation of the mevalonate pathway, and the accumulation of cholesterol in the dystrophic muscles. 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. Conclusions This investigation supports that cholesterol metabolism and the mevalonate pathway are potential therapeutic targets in DMD. |
| first_indexed | 2024-04-24T08:14:30Z |
| format | Article |
| id | doaj.art-f5d408807f4241a8853b7739e99b7ed0 |
| institution | Directory Open Access Journal |
| issn | 2190-5991 2190-6009 |
| language | English |
| last_indexed | 2024-04-24T08:14:30Z |
| publishDate | 2021-06-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of Cachexia, Sarcopenia and Muscle |
| spelling | doaj.art-f5d408807f4241a8853b7739e99b7ed02024-04-17T04:44:51ZengWileyJournal of Cachexia, Sarcopenia and Muscle2190-59912190-60092021-06-0112367769310.1002/jcsm.12708Cholesterol metabolism is a potential therapeutic target in Duchenne muscular dystrophyFatima Amor0Ai Vu Hong1Guillaume Corre2Mathilde Sanson3Laurence Suel4Stephanie Blaie5Laurent Servais6Thomas Voit7Isabelle Richard8David Israeli9Généthon Evry FranceGénéthon Evry FranceGénéthon Evry FranceGénéthon Evry FranceGénéthon Evry FranceGénéthon Evry FranceMDUK Oxford Neuromuscular Center, Department of Paediatrics, University of Oxford, UK & Division of Child Neurology, Centre de Référence des Maladies Neuromusculaires, Department of Paediatrics University Hospital of Liège & University of Liège Liège BelgiumNIHR Great Ormond Street Hospital Biomedical Research Centre and Great Ormond Street Institute of Child Health University College London London UKGénéthon Evry FranceGénéthon Evry FranceAbstract Background Duchenne 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 links the cytoskeleton and the extracellular matrix in skeletal and cardiac muscles. The primary consequence of the disrupted link between the extracellular matrix and the myofibre actin cytoskeleton is thought to involve sarcolemma destabilization, perturbation of Ca2+ 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 are yet poorly understood. In this study, we characterized a molecular mechanism of metabolic perturbation in DMD. Methods We sequenced plasma miRNA in a DMD cohort, comprising 54 DMD patients treated or not by glucocorticoid, compared with 27 healthy controls, in three groups of the ages of 4–8, 8–12, and 12–20 years. We developed an original approach for the biological interpretation of miRNA dysregulation and produced a novel hypothesis concerning metabolic perturbation in DMD. We used the mdx mouse model for DMD for the investigation of this hypothesis. Results We identified 96 dysregulated miRNAs (adjusted P‐value <0.1), of which 74 were up‐regulated and 22 were 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 (SREBP‐1 and SREBP‐2), perturbation of the mevalonate pathway, and the accumulation of cholesterol in the dystrophic muscles. 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. Conclusions This investigation supports that cholesterol metabolism and the mevalonate pathway are potential therapeutic targets in DMD.https://doi.org/10.1002/jcsm.12708Duchenne muscular dystrophyHost geneBiological interpretation of miRNA dysregulationSREBP‐1SREBP‐2Lipid metabolism |
| spellingShingle | Fatima Amor Ai Vu Hong Guillaume Corre Mathilde Sanson Laurence Suel Stephanie Blaie Laurent Servais Thomas Voit Isabelle Richard David Israeli Cholesterol metabolism is a potential therapeutic target in Duchenne muscular dystrophy Journal of Cachexia, Sarcopenia and Muscle Duchenne muscular dystrophy Host gene Biological interpretation of miRNA dysregulation SREBP‐1 SREBP‐2 Lipid metabolism |
| title | Cholesterol metabolism is a potential therapeutic target in Duchenne muscular dystrophy |
| title_full | Cholesterol metabolism is a potential therapeutic target in Duchenne muscular dystrophy |
| title_fullStr | Cholesterol metabolism is a potential therapeutic target in Duchenne muscular dystrophy |
| title_full_unstemmed | Cholesterol metabolism is a potential therapeutic target in Duchenne muscular dystrophy |
| title_short | Cholesterol metabolism is a potential therapeutic target in Duchenne muscular dystrophy |
| title_sort | cholesterol metabolism is a potential therapeutic target in duchenne muscular dystrophy |
| topic | Duchenne muscular dystrophy Host gene Biological interpretation of miRNA dysregulation SREBP‐1 SREBP‐2 Lipid metabolism |
| url | https://doi.org/10.1002/jcsm.12708 |
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