Identification of hub genes related to Duchenne muscular dystrophy by weighted gene co-expression network analysis

Wei, Yanning; Su, Qingde; Li, Xiaohong

doi:10.1097/md.0000000000032603

Cited by 2 publications

(2 citation statements)

References 27 publications

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“…It plays an important role in suppressing inflammatory responses. It was previously identified as a hub gene in a microarray database of DMD muscle samples (GSE6011) 9 . The preservation of this hub gene in advanced stage DMD muscle suggests an ongoing role of complement activation in disease progression.…”

Section: Discussionmentioning

confidence: 99%

“…Investigation of disease-driving pathways, regulators, and networks, including BMP4, in severely affected late-stage DMD muscle has been slowed by decreasing use of muscle biopsy and difficulty with animal models reproducing severe dystrophic muscle disease seen in humans. As such, prior studies have largely consisted of array panels in younger DMD muscles [9][10][11][12][13][14] .…”

Section: Introductionmentioning

confidence: 99%

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Late-Stage Skeletal Muscle Transcriptome in Duchenne muscular dystrophy shows a BMP4-Induced Molecular Signature

Sothers,

Hu,

Crossman

et al. 2024

Preprint

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Duchenne muscular dystrophy (DMD) is a fatal X-linked recessive disease due to loss-of-function mutations in the DYSTROPHIN gene. DMD-related skeletal muscle wasting is typified by an aberrant immune response involving upregulation of TGFβ family of cytokines. We previously demonstrated that bone morphogenetic protein 4 (BMP4) is increased in DMD and BMP4 stimulation induces a 20-fold upregulation of Smad8 transcription. However, the role of BMP4 in severely affected DMD skeletal muscle is unknown. We hypothesized that transcriptomic signatures in severely affected human DMD skeletal muscle are driven by BMP4 signaling. Transcriptomes from skeletal muscle biopsies of late-stage DMD vs. non-DMD controls and C2C12 muscle cells with or without BMP4 stimulation were generated by RNA-Seq and analyzed for single transcript differential expression as well as by Ingenuity Pathway Analysis and weighted gene co-expression network analyses. A total of 2,328 and 5,291 transcripts in the human muscle and C2C12 muscle cells, respectively, were differentially expressed. We identified an overlapping molecular signature of 1,027 genes dysregulated in DMD muscle that were induced in BMP4-stimulated C2C12 muscle cells. Highly upregulated DMD transcripts that overlapped with BMP4-stimulated C2C12 muscle cells included ADAMTS3, HCAR2, SERPING1, SMAD8, and UNC13C. The DMD transcriptome was characterized by dysregulation of pathways involving immune function, extracellular matrix remodeling, and metabolic/mitochondrial function. In summary, we define a late-stage DMD skeletal muscle transcriptome that substantially overlaps with the BMP4-induced molecular signature in C2C12 muscle cells. This supports BMP4 as a disease-driving regulator of transcriptomic changes in late-stage DMD skeletal muscle and expands our understanding of the evolution of dystrophic signaling pathways and their associated gene networks that could be explored for therapeutic development.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Late-Stage Skeletal Muscle Transcriptome in Duchenne muscular dystrophy shows a BMP4-Induced Molecular Signature

Sothers,

Hu,

Crossman

et al. 2024

Preprint

View full text Add to dashboard Cite

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Proteomic profiling of human plasma extracellular vesicles identifies PF4 and C1R as novel biomarker in sarcopenia

Aparicio,

Navarrete‐Villanueva,

Gómez‐Cabello

et al. 2024

J cachexia sarcopenia muscle

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BackgroundSarcopenia, the gradual and generalized loss of muscle mass and function with ageing, is one of the major health problems in older adults, given its high prevalence and substantial socioeconomic implications. Despite the extensive efforts to reach consensus on definition and diagnostic tests and cut‐offs for sarcopenia, there is an urgent and unmet need for non‐invasive, specific and sensitive biomarkers for the disease. Extracellular vesicles (EVs) are present in different biofluids including plasma, whose cargo reflects cellular physiology. This work analysed EV proteome in sarcopenia and robust patients in the search for differentially contained proteins that can be used to diagnose the disease.MethodsPlasma small EVs (sEVs) from a total of 29 robust controls (aged 73.4 ± 5.6 years; 11 men and 18 women) and 49 sarcopenic patients (aged 82.3 ± 5.4 years; 15 men and 34 women) aged 65 years and older were isolated and their cargo was analysed by proteomics. Proteins whose concentration in sEVs was different between sarcopenic and robust patients were further validated using ELISA. The concentration of these candidates was correlated to the EWGSOP2 sarcopenia tests for low muscle strength and low physical performance, and receiver operating characteristic (ROC) curve analyses were carried out to evaluate their diagnostic power, sensitivity and specificity.ResultsProteomic analysis identified 157 sEVs proteins in both sarcopenic and robust samples. Among them, 48 proteins had never been reported in the ExoCarta nor Vesiclepedia databases. Statistical analysis revealed eight proteins whose concentration was significantly different between groups: PF4 (log2 FC = 4.806), OIT3 (log2 FC = −1.161), MMRN1 (log2 FC = −1.982), MASP1 (log2 FC = −0.627), C1R (log2 FC = 1.830), SVEP1 (log2 FC = 1.295), VCAN (FC = 0.937) and SPTB (log2 FC = 1.243). Among them, platelet factor 4 (PF4) showed the lowest concentration while Complement C1r subcomponent (C1R) increased the most in sarcopenic patients, being these results confirmed by ELISA (P = 1.07E‐09 and P = 0.001287, respectively). The concentrations of candidate proteins significantly correlated with EWGSOP2 tests currently used. ROC curve analysis showed an area under the curve of 0.8921 and 0.7476 for PF4 and C1R, respectively. Choosing the optimal for PF4, 80% sensitivity and 85.71% specificity was reached while the optimal cut‐off value of C1R would allow sarcopenia diagnosis with 75% sensitivity and 66.67% specificity.ConclusionsOur results support the determination of EV PF4 and C1R as plasma diagnostic biomarkers in sarcopenia and open the door to investigate the role of the content of these vesicles in the pathogeny of the disease.

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Identification of hub genes related to Duchenne muscular dystrophy by weighted gene co-expression network analysis

Cited by 2 publications

References 27 publications

Late-Stage Skeletal Muscle Transcriptome in Duchenne muscular dystrophy shows a BMP4-Induced Molecular Signature

Late-Stage Skeletal Muscle Transcriptome in Duchenne muscular dystrophy shows a BMP4-Induced Molecular Signature

Proteomic profiling of human plasma extracellular vesicles identifies PF4 and C1R as novel biomarker in sarcopenia

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