DUX4 expression activates JNK and p38 MAP kinases in myoblasts

Area of Science:

• Molecular Biology
• Cellular Physiology
• Genetics

Background:

• Facioscapulohumeral muscular dystrophy (FSHD) is linked to DUX4 transcription factor misexpression in skeletal muscle.
• DUX4 misexpression leads to transcriptional changes, cellular abnormalities, and myoblast death.

Purpose of the Study:

• To investigate the temporal dynamics of cellular stress following DUX4 activation.
• To identify key signaling pathways involved in DUX4-induced cellular damage and death.

Main Methods:

• Longitudinal RNA sequencing, proteomics, and phosphoproteomics were employed in DUX4-expressing myoblasts.
• Analysis focused on cellular physiology, DNA damage, mRNA splicing, and protein phosphorylation patterns.
• Investigated the role of stress-responsive MAP kinase pathways (JNK and p38) in DUX4 toxicity.

Main Results:

• DUX4 activation induced significant changes in cellular physiology, including DNA damage and altered mRNA splicing.
• Rapid and widespread protein phosphorylation changes indicated altered kinase signaling.
• The JNK and p38 MAP kinase pathways were activated by DUX4 expression.
• Inhibition of JNK and p38 pathways reduced DUX4-mediated myoblast cell death.

Conclusions:

• The JNK pathway is implicated in DUX4-mediated cell death in FSHD.
• These findings offer further insights into the p38 pathway's role in FSHD pathogenesis.
• Targeting these kinase pathways may represent a therapeutic strategy for FSHD.