Epigenetic changes as a common trigger of muscle weakness in congenital myopathies

TY - JOUR

T1 - Epigenetic changes as a common trigger of muscle weakness in congenital myopathies

AU - Rokach, Ori

AU - Sekulic-Jablanovic, Marijana

AU - Voermans, Nicol

AU - Wilmshurst, Jo

AU - Pillay, Komala

AU - Heytens, Luc

AU - Zhou, Haiyan

AU - Muntoni, Francesco

AU - Gautel, Mathias

AU - Nevo, Yoram

AU - Mitrani-Rosenbaum, Stella

AU - Attali, Ruben

AU - Finotti, Alessia

AU - Gambari, Roberto

AU - Mosca, Barbara

AU - Jungbluth, Heinz

AU - Zorzato, Francesco

AU - Treves, Susan

N1 - © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected].

PY - 2015/5/27

Y1 - 2015/5/27

N2 - Congenital myopathies are genetically and clinically heterogeneous conditions causing severe muscle weakness, and mutations in the ryanodine receptor gene (RYR1) represent the most frequent cause of these conditions. A common feature of diseases caused by recessive RYR1 mutations is a decrease of ryanodine receptor 1 protein content in muscle. The aim of the present investigation was to gain mechanistic insight into the causes of this reduced ryanodine receptor 1. We found that muscle biopsies of patients with recessive RYR1 mutations exhibit decreased expression of muscle-specific microRNAs, increased DNA methylation and increased expression of class II histone deacetylases. Transgenic mouse muscle fibres over-expressing HDAC-4/HDAC-5 exhibited decreased expression of RYR1 and of muscle-specific miRNAs, whereas acute knock-down of RYR1 in mouse muscle fibres by siRNA caused up-regulation of HDAC-4/HDAC-5. Intriguingly, increased class II HDAC expression and decreased ryanodine receptor protein and miRNAs expression were also observed in muscles of patients with nemaline myopathy, another congenital neuromuscular disorder. Our results indicate that a common pathophysiological pathway caused by epigenetic changes is activated in some forms of congenital neuromuscular disorders.

AB - Congenital myopathies are genetically and clinically heterogeneous conditions causing severe muscle weakness, and mutations in the ryanodine receptor gene (RYR1) represent the most frequent cause of these conditions. A common feature of diseases caused by recessive RYR1 mutations is a decrease of ryanodine receptor 1 protein content in muscle. The aim of the present investigation was to gain mechanistic insight into the causes of this reduced ryanodine receptor 1. We found that muscle biopsies of patients with recessive RYR1 mutations exhibit decreased expression of muscle-specific microRNAs, increased DNA methylation and increased expression of class II histone deacetylases. Transgenic mouse muscle fibres over-expressing HDAC-4/HDAC-5 exhibited decreased expression of RYR1 and of muscle-specific miRNAs, whereas acute knock-down of RYR1 in mouse muscle fibres by siRNA caused up-regulation of HDAC-4/HDAC-5. Intriguingly, increased class II HDAC expression and decreased ryanodine receptor protein and miRNAs expression were also observed in muscles of patients with nemaline myopathy, another congenital neuromuscular disorder. Our results indicate that a common pathophysiological pathway caused by epigenetic changes is activated in some forms of congenital neuromuscular disorders.

U2 - 10.1093/hmg/ddv195

DO - 10.1093/hmg/ddv195

M3 - Article

C2 - 26019235

SN - 0964-6906

JO - Human Molecular Genetics

JF - Human Molecular Genetics

ER -