2. Academic Validation
  3. DUX4 expression activates JNK and p38 MAP kinases in myoblasts

DUX4 expression activates JNK and p38 MAP kinases in myoblasts

  • Dis Model Mech. 2022 Oct 5;dmm.049516. doi: 10.1242/dmm.049516.
Christopher M Brennan 1 2,  Abby S Hill 1,  Michael St Andre 1,  Xianfeng Li 1,  Vijaya Madeti 3,  Susanne Breitkopf 4,  Seth Garren 3,  Liang Xue 5,  Tamara Gilbert 6,  Angela Hadjipanayis 3,  Mara Monetti 4,  Charles P Emerson 7,  Robert Moccia 1,  Jane Owens 1,  Nicolas Christoforou 1
Affiliations

Affiliations

  • 1 Rare Disease Research Unit, Pfizer Inc., Cambridge, MA, USA.
  • 2 WRDM Postdoctoral Program, Pfizer Inc., Cambridge, MA, USA.
  • 3 NGS Technology Center, Inflammation and Immunology Research Unit, Pfizer, Cambridge, MA, USA.
  • 4 Proteomics Technology Center, Internal Medicine Research Unit, Pfizer, Cambridge, MA, USA.
  • 5 Machine Learning and Computational Science, Pfizer Inc., Cambridge, MA, USA.
  • 6 High Content Imaging Technology Center, Internal Medicine Research Unit, Pfizer, Cambridge, MA, USA.
  • 7 Wellstone Muscular Dystrophy Program, Department of Neurology, University of Massachusetts Medical School, Worcester, MA, USA.
PMID: 36196640 DOI: 10.1242/dmm.049516
Abstract

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 paired with proteomics and phosphoproteomics. 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.

Keywords

MAP kinase signaling; Muscular dystrophy; Phosphoproteomics.

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