title: Epigenetic changes as a common trigger of muscle weakness in congenital myopathies.
abstract: 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.
authors.affiliation: Department of Biomedicine and Anesthesia, Basel University Hospital, Basel, Switzerland.
authors.forename: Ori
authors.initials: O
authors.lastname: Rokach
authors.affiliation: Department of Biomedicine and Anesthesia, Basel University Hospital, Basel, Switzerland.
authors.forename: Marijana
authors.initials: M
authors.lastname: Sekulic-Jablanovic
authors.affiliation: Department of Neurology, Roadboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Nicol
authors.initials: N
authors.lastname: Voermans
authors.affiliation: Department of Paediatric Neurology and Child Health.
authors.forename: Jo
authors.initials: J
authors.lastname: Wilmshurst
authors.affiliation: Department of Paediatric Pathology, NHLS, Cape Town, South Africa, Department of Paediatrics and Child Health, University of Cape Town, Red Cross Children's Hospital, Cape Town, South Africa.
authors.forename: Komala
authors.initials: K
authors.lastname: Pillay
authors.affiliation: Department of Anesthesiology and Neurology, Antwerp University Hospital, Antwerp, Belgium.
authors.forename: Luc
authors.initials: L
authors.lastname: Heytens
authors.affiliation: Dubowitz Neuromuscular Centre and MRC Centre for Neuromuscular Diseases, Institute of Child Health, London, UK.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Dubowitz Neuromuscular Centre and MRC Centre for Neuromuscular Diseases, Institute of Child Health, London, UK.
authors.forename: Francesco
authors.initials: F
authors.lastname: Muntoni
authors.affiliation: Randall Division of Cell and Molecular Biophysics and Cardiovascular Division, King's College London, London, UK.
authors.forename: Mathias
authors.initials: M
authors.lastname: Gautel
authors.affiliation: The Unit of Neuropediatrics and Child Development, Division of Pediatrics.
authors.forename: Yoram
authors.initials: Y
authors.lastname: Nevo
authors.affiliation: Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Stella
authors.initials: S
authors.lastname: Mitrani-Rosenbaum
authors.affiliation: Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Ruben
authors.initials: R
authors.lastname: Attali
authors.affiliation: Department of Life Sciences, Section of Biochemistry and Molecular Biology.
authors.forename: Alessia
authors.initials: A
authors.lastname: Finotti
authors.affiliation: Department of Life Sciences, Section of Biochemistry and Molecular Biology.
authors.forename: Roberto
authors.initials: R
authors.lastname: Gambari
authors.affiliation: Department of Life Sciences, General Pathology Section, University of Ferrara, Ferrara, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Mosca
authors.affiliation: Department of Paediatric Neurology, Neuromuscular Service, Evelina Children's Hospital, St. Thomas' Hospital, London, UK and Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King's College London, London, UK.
authors.forename: Heinz
authors.initials: H
authors.lastname: Jungbluth
authors.affiliation: Department of Biomedicine and Anesthesia, Basel University Hospital, Basel, Switzerland, Department of Life Sciences, General Pathology Section, University of Ferrara, Ferrara, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Zorzato
authors.affiliation: Department of Biomedicine and Anesthesia, Basel University Hospital, Basel, Switzerland, Department of Life Sciences, General Pathology Section, University of Ferrara, Ferrara, Italy, susan.treves@unibas.ch.
authors.forename: Susan
authors.initials: S
authors.lastname: Treves
mesh_terms: D000818:Animals; D044127:Epigenesis, Genetic; D006655:Histone Deacetylases / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D018908:Muscle Weakness / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009154:Mutation; D009224:Myotonia Congenita / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D019837:Ryanodine Receptor Calcium Release Channel / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D019837:Ryanodine Receptor Calcium Release Channel; C000592747:ryanodine receptor 1, mouse; C498618:Hdac5 protein, mouse; D006655:Histone Deacetylases