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Transcriptomic Profile of Skeletal Muscle Biopsies from Duchenne and Becker Muscular Dystrophy Patients

ABSTRACT: The complexity of RNA metabolism has become crucial in neuromuscular diseases, especially for Duchenne Muscular Dystrophy (DMD) and Becker Muscular Dystrophy (BMD). DMD is associated with mutations in Dystrophin gene that disrupt the protein reading frame causing premature stop codons. In contrast, patients with BMD usually have in-frame deletions that maintain the correct reading frame. Our goal is to search for possible pathways that differs between the two diseases, in which DMD develop a severe phenotype compared to BMD. Here we aimed to evaluate the transcriptomic profile in muscle biopsy of DMD and BMD patients. We collected RNA obtained from muscle biopsy of pediatric DMD patients (n=12) and BMD patients (n=6). Through RNA sequencing, the differentially expressed (DE) genes of DMD patients versus BMD patients were analyzed. Through principal component analysis (PCA), we were able to identify a clear difference between the two groups based on gene expression pattern. DMD patients compared to BMD patients showed a particular activation of genes involved in collagen synthesis, extracellular matrix organization, and oncostatin M-dependent pathways, which plays an important role in the fibrosis process. This suggests that a more severe phenotype in DMD than BMD patients may be due to greater deregulation of these pathways, reflecting the clinical picture of patients observed. Furthermore mRNAs expression levels evaluated by RT-qPCR confirmed RNA-seq data. Enrichment pathways analysis revealed the strong alteration in collagen synthesis and extracellular matrix organization, suggesting different severity degree in the establishment of fibrotic processes. All the collagen genes validated by RT-qPCR were strongly upregulated in DMD patients. This study provides preliminary insights into the difference in gene expression between the two groups and lays the basis for the identification of possible mechanism that differentiate between the two diseases.

ORGANISM(S): Homo sapiens

PROVIDER: GSE291383 | GEO | 2025/07/30

REPOSITORIES: GEO

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Project description:Absence of the dystrophin gene in Duchenne muscular dystrophy (DMD) results in the degeneration of skeletal and cardiac muscles. Owing to advances in respiratory medicine, cardiomyopathy has become a significant aspect of the disease. While CRISPR/Cas9 genome editing technology holds great potential as a novel therapeutic avenue for DMD, little is known about the efficacy of correction of DMD using the CRISPR/Cas9 system in mitigating the cardiomyopathy phenotype in DMD. To define the effects of CRISPR/Cas9 genome editing on structural, functional and transcriptional dysregulation in DMD-associated cardiomyopathy. We generated induced pluripotent stem cells (iPSCs) from a patient with a deletion of exon 44 of the DMD gene (ΔEx44) and his healthy brother. Here, we targeted exon 45 of the DMD gene by CRISPR/Cas9 genome editing to generate corrected DMD (cDMD) iPSC lines, wherein the DMD open reading frame was restored via reframing (RF) or exon skipping (ES). While DMD cardiomyocytes (CMs) demonstrated morphologic, structural and functional deficits compared to control CMs, CMs from both cDMD lines were similar to control CMs. Bulk RNA-sequencing of DMD CMs showed transcriptional dysregulation consistent with dilated cardiomyopathy, which was mitigated in cDMD CMs. We then corrected DMD CMs by adenoviral delivery of Cas9/gRNA and showed that postnatal correction of DMD CMs reduces their arrhythmogenic potential. Single-nucleus RNA-sequencing of hearts showed reduced transcriptional dysregulation in CMs and fibroblasts in corrected mice compared with DMD mice, consistent with reduced histopathologic changes.We show that CRISPR/Cas9-mediated correction of DMD ΔEx44 mitigates structural, functional and transcriptional dysregulation consistent with dilated cardiomyopathy irrespective of how the protein reading frame is restored. We show that these effects extend to postnatal editing in iPSC-CMs and mice. These findings provide key insights into the utility of genome editing as a novel therapeutic for DMD-associated cardiomyopathy.

Project description:Rationale – Absence of the dystrophin gene in Duchenne muscular dystrophy (DMD) results in the degeneration of skeletal and cardiac muscles. Owing to advances in respiratory medicine, cardiomyopathy has become a significant aspect of the disease. While CRISPR/Cas9 genome editing technology holds great potential as a novel therapeutic avenue for DMD, little is known about the efficacy of correction of DMD using the CRISPR/Cas9 system in mitigating the cardiomyopathy phenotype in DMD. Objective – To define the effects of CRISPR/Cas9 genome editing on structural, functional and transcriptional dysregulation in DMD-associated cardiomyopathy. Methods and Results – We generated induced pluripotent stem cells (iPSCs) from a patient with a deletion of exon 44 of the DMD gene (ΔEx44) and his healthy brother. Here, we targeted exon 45 of the DMD gene by CRISPR/Cas9 genome editing to generate corrected DMD (cDMD) iPSC lines, wherein the DMD open reading frame was restored via reframing (RF) or exon skipping (ES). While DMD cardiomyocytes (CMs) demonstrated morphologic, structural and functional deficits compared to control CMs, CMs from both cDMD lines were similar to control CMs. Bulk RNA-sequencing of DMD CMs showed transcriptional dysregulation consistent with dilated cardiomyopathy, which was mitigated in cDMD CMs. We then corrected DMD CMs by adenoviral delivery of Cas9/gRNA and showed that postnatal correction of DMD CMs reduces their arrhythmogenic potential. Single-nucleus RNA-sequencing of hearts showed reduced transcriptional dysregulation in CMs and fibroblasts in corrected mice compared with DMD mice, consistent with reduced histopathologic changes. Conclusions – We show that CRISPR/Cas9-mediated correction of DMD ΔEx44 mitigates structural, functional and transcriptional dysregulation consistent with dilated cardiomyopathy irrespective of how the protein reading frame is restored. We show that these effects extend to postnatal editing in iPSC-CMs and mice. These findings provide key insights into the utility of genome editing as a novel therapeutic for DMD-associated cardiomyopathy.

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Transcriptomic Profile of Skeletal Muscle Biopsies from Duchenne and Becker Muscular Dystrophy Patients

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