DUX4 expression activates JNK and p38 MAP kinases in myoblasts: MAJIQ splicing results

Facioscapulohumoral muscular dystrophy (FSHD) is caused by misexpression
of the DUX4 transcription factor in skeletal muscle that results in
transcriptional alterations, abnormal phenotypes, and cell death. To gain
insight into the kinetics of DUX4-induced stresses, we activated DUX4
expression in myoblasts and performed longitudinal RNA sequencing (GEO
GSE205421) paired with proteomics and phosphoproteomics
(MassIVE MSV000089812). This analysis revealed changes in
cellular physiology including DNA damage and altered mRNA splicing.
Phosphoproteomic analysis uncovered widespread changes in protein
phosphorylation rapidly following DUX4 induction indicating that
alterations in kinase signaling may play a role in DUX4-mediated stress
and cell death. Indeed, we demonstrate that two stress-responsive MAP
kinase pathways, JNK and p38, are activated in response to DUX4
expression. Inhibition of each of these pathways ameliorated DUX4-mediated
cell death in myoblasts. These findings uncover JNK as a novel pathway
involved in DUX4-mediated cell death as well as provide additional
insights into the role of the p38 pathway, a clinical target for the
treatment of FSHD.