Late-Stage Skeletal Muscle Transcriptome in Duchenne Muscular Dystrophy Shows a BMP4-Induced Molecular Signature.

Area of Science:

• Molecular Biology
• Genetics
• Biochemistry

Background:

• Duchenne muscular dystrophy (DMD) involves loss-of-function variants in the DYSTROPHIN gene, leading to skeletal muscle wasting.
• Aberrant immune responses, including TGFβ cytokine upregulation (e.g., TGFβ1, BMP4), characterize DMD muscle pathology.
• Previous work showed BMP4 stimulation increases Smad8 transcription in muscle cells.

Purpose of the Study:

• To investigate the role of BMP4 signaling in late-stage DMD skeletal muscle.
• To identify a transcriptomic signature associated with BMP4 signaling in DMD.
• To test the hypothesis that BMP4 signaling drives aberrant gene expression in late-stage DMD.

Main Methods:

• RNA-Seq was used to generate transcriptomes from skeletal muscle biopsies of late-stage DMD patients and non-DMD controls.
• C2C12 muscle cells were stimulated with BMP4 to compare transcriptomic profiles.
• Ingenuity Pathway Analysis, WGCNA, and GSEA were employed to analyze transcriptional differences.

Main Results:

• A significant overlap of 1027 dysregulated genes was found between DMD muscle and BMP4-stimulated C2C12 cells.
• SERPING1 and Aff3 were identified as key hub genes.
• DMD muscle exhibited upregulated TGFβ signaling, ECM remodeling, and collagen biosynthesis, with inhibited mitochondrial pathways.

Conclusions:

• The DMD transcriptome is characterized by dysregulated immune function, ECM remodeling, and muscle bioenergetic metabolism.
• A late-stage DMD skeletal muscle transcriptome signature overlaps with BMP4-induced changes in C2C12 cells.
• The BMP4/Smad8 pathway is implicated as a disease-driving regulator in late-stage DMD, suggesting potential therapeutic targets.