Clarke, Brian, Cruz Jr, Joseph, Wilson, Liz, Hupper, Nicole, Wang, Yuan, Patora-Komisarska, Krystyna, Oberhauser, Berndt, Concannon, John, Glass, David, Trendelenburg, Anne-Ulrike and Zhang, Yunyu (2018) Protein kinase A activation inhibits DUX4 gene expression in facioscapulohumeral muscular dystrophy patient myotubes. Journal of Biological Chemistry. ISSN 0021-92581083-351X

Abstract

Facioscapulohumeral muscular dystrophy (FSHD) is among the most prevalent of the adult onset muscular dystrophies. FSHD causes the loss of muscle mass and function resulting in severe debilitation and reduction in quality of life. Currently only the symptoms of FSHD can be treated and with minimal benefit. The available options are not curative and none of the treatments address the underlying cause of FSHD. Given that the genetic, epigenetic and molecular mechanisms underlying FSHD are now quite well understood and that DUX4 expression has been demonstrated to be necessary for disease onset and is largely thought to be the causative factor in FSHD, we sought to identify compounds modulating Dux4 activity in a phenotypic screen using FSHD patient derived muscle cells. This effort has led to the identification of molecules able to reduce DUX4 gene expression and hence Dux4 activity. Amongst those, β-2 adrenergic receptor agonists and phosphodiesterase inhibitors, both leading to increased cellular cAMP, were particularly effective in patient cells. We further determined that cAMP production reduces DUX4 expression through a PKA dependent mode of action in FSHD patient myotubes. These findings increase our understanding of DUX4 expression regulation in FSHD and point to potential areas of therapeutic intervention.

Item Type:	Article
Date Deposited:	03 Jul 2018 00:45
Last Modified:	03 Jul 2018 00:45
URI:	https://oak.novartis.com/id/eprint/35309