High prevalence of plasma lipid abnormalities in human and canine Duchenne and Becker muscular dystrophies depicts a new type of primary genetic dyslipidemia

White, Zoe; Hakim, Chady H.; Théret, Marine; Yang, N. Nora; Rossi, Fábio; Cox, Dan; Straub, V.; Selby, Kathryn; Panagiotopoulos, Constadina; Duan, Dongsheng; Bernatchez, Pascal

doi:10.1016/j.jacl.2020.05.098

Cited by 21 publications

(39 citation statements)

References 48 publications

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“…Our results support that HMGCR and the accumulation of cholesterol in the muscle are the direct therapeutic targets of simvastatin in DMD. This proposition is in agreement with earlier reports of lipid and particularly of cholesterol metabolism abnormalities in DMD 11,50–53 . Of particular interest, Steen et al .…”

Section: Discussionsupporting

confidence: 93%

“…reported the correlation between increased plasma cholesterol and accentuated muscular dystrophy in the mdx mouse, 53 and most recently White et al . reported the high prevalence of plasma lipid abnormalities in DMD patients, 52 which together support that perturbation of cholesterol metabolism affects the DMD phenotype. Not only does our study concords with these previous findings, it also provides a molecular framework for this dysregulation.…”

Section: Discussionmentioning

confidence: 77%

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Cholesterol metabolism is a potential therapeutic target in Duchenne muscular dystrophy

Amor

Hong

Corre

et al. 2021

J cachexia sarcopenia muscle

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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.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 77%

Cholesterol metabolism is a potential therapeutic target in Duchenne muscular dystrophy

Amor

Hong

Corre

et al. 2021

J cachexia sarcopenia muscle

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“…The copyright holder for this preprint this version posted January 21, 2021. ; https://doi.org/10.1101/2021.01.20.427485 doi: bioRxiv preprint demonstrated that Nilotinib strongly inhibits fibrosis in the muscle and the heart after acute damage [15,61], Nilotinib administration has been associated with adverse effects such as hyperglycemia, increased LDL and HDL, vascular and cardiovascular toxicity when used in the context of long-term treatment [62]. Very recently, White et al, demonstrated that DMD and Becker muscular dystrophy (BMD) patients displayed plasma lipid abnormalities early in the onset of the disease [63]. In addition, in vitro, Nilotinib inhibits C2C12 myoblast differentiation [64].…”

Section: Testing Anti-fibrotic Drugs Candidates In Vivomentioning

confidence: 99%

Targeting fibrosis in the Duchenne Muscular Dystrophy mice model: an uphill battle

Théret¹,

M²,

Rempel³

et al. 2021

Preprint

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AimFibrosis is the most common complication from chronic diseases, and yet no therapy capable of mitigating its effects is available. Our goal is to unveil specific signallings regulating the fibrogenic process and to identify potential small molecule candidates that block fibrogenic differentiation of fibro/adipogenic progenitors.MethodWe performed a large-scale drug screen using muscle-resident fibro/adipogenic progenitors from a mouse model expressing EGFP under the Collagen1a1 promotor. We first confirmed that the EGFP was expressed in response to TGFβ1 stimulation in vitro. Then we treated cells with TGFβ1 alone or with drugs from two libraries of known compounds. The drugs ability to block the fibrogenic differentiation was quantified by imaging and flow cytometry. From a two-rounds screening, positive hits were tested in vivo in the mice model for the Duchenne muscular dystrophy (mdx mice). The histopathology of the muscles was assessed with picrosirius red (fibrosis) and laminin staining (myofiber size).Key findingsFrom the in vitro drug screening, we identified 21 drugs and tested 3 in vivo on the mdx mice. None of the three drugs significantly improved muscle histopathology.SignificanceThe in vitro drug screen identified various efficient compounds, none of them strongly inhibited fibrosis in skeletal muscle of mdx mice. To explain these observations, we hypothesize that in Duchenne Muscular Dystrophy, in which fibrosis is a secondary event due to chronic degeneration and inflammation, the drugs tested could have adverse effect on regeneration or inflammation, balancing off any positive effects and leading to the absence of significant results.

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“…A series of diseases were correlated to the atrophy of skeletal muscles and leading to dysfunction of muscular organs such as Duchenne muscular dystrophy (DMD), degenerative rotator cuff tear, etc. [5][6][7]. Stem cells are promising cells that have the potency of multidirectional differentiation and proliferation and are widely expected to be used in the field of tissue repair and regeneration [8,9].…”

Section: Introductionmentioning

confidence: 99%

Identification of key pathways and hub genes in the myogenic differentiation of pluripotent stem cell: a bioinformatics and experimental study

et al. 2021

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Background The regeneration of muscle cells from stem cells is an intricate process, and various genes are included in the process such as myoD, mf5, mf6, etc. The key genes and pathways in the differentiating stages are various. Therefore, the differential expression of key genes after 4 weeks of differentiation were investigated in our study. Method Three published gene expression profiles, GSE131125, GSE148994, and GSE149055, about the comparisons of pluripotent stem cells to differentiated cells after 4 weeks were obtained from the Gene Expression Omnibus (GEO) database. Common differentially expressed genes (DEGs) were obtained for further analysis such as protein-protein interaction (PPI) network, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and GSEA analysis. After hub genes and key pathways were obtained, we manipulated in vitro cell research for substantiation such as immunohistochemical staining and semi-quantitative analysis and quantitative real-time PCR. Results A total of 824 DEGs including 350 upregulated genes and 474 downregulated genes were identified in the three GSEs. Nineteen hub genes were identified from the PPI network. The GO and KEGG pathway analyses confirmed that myogenic differentiation at 4 weeks was strongly associated with pathway in cancer, PI3K pathway, actin cytoskeleton regulation and metabolic pathway, biosynthesis of antibodies, and cell cycle. GSEA analysis indicated the differentiated cells were enriched in muscle cell development and myogenesis. Meanwhile, the core genes in each pathway were identified from the GSEA analysis. The in vitro cell research revealed that actin cytoskeleton and myoD were upregulated after 4-week differentiation. Conclusions The research revealed the potential hub genes and key pathways after 4-week differentiation of stem cells which contribute to further study about the molecular mechanism of myogenesis regeneration, paving a way for more accurate treatment for muscle dysfunction.

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High prevalence of plasma lipid abnormalities in human and canine Duchenne and Becker muscular dystrophies depicts a new type of primary genetic dyslipidemia

Cited by 21 publications

References 48 publications

Cholesterol metabolism is a potential therapeutic target in Duchenne muscular dystrophy

Cholesterol metabolism is a potential therapeutic target in Duchenne muscular dystrophy

Targeting fibrosis in the Duchenne Muscular Dystrophy mice model: an uphill battle

Identification of key pathways and hub genes in the myogenic differentiation of pluripotent stem cell: a bioinformatics and experimental study

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