RT Journal Article
SR Electronic
T1 P38&#945 Regulates Expression of DUX4 in a Model of Facioscapulohumeral Muscular Dystrophy
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP jpet.119.264689
DO 10.1124/jpet.119.264689
A1 Luis A Rojas
A1 Erin Valentine
A1 Anthony Accorsi
A1 Joseph Maglio
A1 Ning Shen
A1 Alan Robertson
A1 Steven Kazmirski
A1 Peter Rahl
A1 Rabi Tawil
A1 Diego Cadavid
A1 Lorin A Thompson
A1 Lucienne Ronco
A1 Aaron Chang
A1 Angela Cacace
A1 Owen Wallace
YR 2020
UL http://jpet.aspetjournals.org/content/early/2020/07/16/jpet.119.264689.abstract
AB FSHD is caused by the loss of repression at the D4Z4 locus leading to DUX4 expression in skeletal muscle, activation of its early embryonic transcriptional program and muscle fiber death. While progress toward understanding the signals driving DUX4 expression has been made, the factors and pathways involved in the transcriptional activation of this gene remain largely unknown. Here, we describe the identification and characterization of p38α as a novel regulator of DUX4 expression in FSHD myotubes. By using multiple highly characterized, potent and specific inhibitors of p38α/β, we show a robust reduction of DUX4 expression, activity and cell death across FSHD1 and FSHD2 patient-derived lines. RNA-seq profiling reveals that a small number of genes are differentially expressed upon p38α/β inhibition, the vast majority of which are DUX4 target genes. Our results reveal a novel and apparently critical role for p38α in the aberrant activation of DUX4 in FSHD and support the potential of p38α/β inhibitors as effective therapeutics to treat FSHD at its root cause.SIGNIFICANCE STATEMENT Using patient-derived FSHD myotubes, we characterize the pharmacological relationships between p38α/β inhibition, DUX4 expression, its downstream transcriptional program and muscle cell death. p38α/β inhibition results in potent and specific DUX4 downregulation across multiple genotypes without significant effects in the process of myogenesis in vitro. These findings highlight the potential of p38α/β inhibitors for the treatment of FSHD a condition that today has no approved treatments.