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

Hum Mol Genet. 2015 Aug 15;24(16):4636-47. doi: 10.1093/hmg/ddv195. Epub 2015 May 27.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Epigenesis, Genetic*
  • Histone Deacetylases / biosynthesis*
  • Histone Deacetylases / genetics
  • Mice
  • Muscle Weakness / genetics
  • Muscle Weakness / metabolism*
  • Muscle Weakness / pathology
  • Mutation
  • Myotonia Congenita / genetics
  • Myotonia Congenita / metabolism*
  • Myotonia Congenita / pathology
  • Ryanodine Receptor Calcium Release Channel / biosynthesis*
  • Ryanodine Receptor Calcium Release Channel / genetics


  • Ryanodine Receptor Calcium Release Channel
  • ryanodine receptor 1, mouse
  • Hdac5 protein, mouse
  • Histone Deacetylases