title: Cellular, biochemical and molecular changes in muscles from patients with X-linked myotubular myopathy due to MTM1 mutations.
abstract: Centronuclear myopathies are early-onset muscle diseases caused by mutations in several genes including MTM1, DNM2, BIN1, RYR1 and TTN. The most severe and often fatal X-linked form of myotubular myopathy (XLMTM) is caused by mutations in the gene encoding the ubiquitous lipid phosphatase myotubularin, an enzyme specifically dephosphorylating phosphatidylinositol-3-phosphate and phosphatidylinositol-3,5-bisphosphate. Because XLMTM patients have a predominantly muscle-specific phenotype a number of pathogenic mechanisms have been proposed, including a direct effect of the accumulated lipid on the skeletal muscle calcium channel ryanodine receptor 1, a negative effect on the structure of intracellular organelles and defective autophagy. Animal models knocked out for MTM1 show severe reduction of ryanodine receptor 1 mediated calcium release but, since knocking out genes in animal models does not necessarily replicate the human phenotype, we considered it important to study directly the effect of MTM1 mutations on patient muscle cells. The results of the present study show that at the level of myotubes MTM1 mutations do not dramatically affect calcium homeostasis and calcium release mediated through the ryanodine receptor 1, though they do affect myotube size and nuclear content. On the other hand, mature muscles such as those obtained from patient muscle biopsies exhibit a significant decrease in expression of the ryanodine receptor 1, a decrease in muscle-specific microRNAs and a considerable up-regulation of histone deacetylase-4. We hypothesize that the latter events consequent to the primary genetic mutation, are the cause of the severe decrease in muscle strength that characterizes these patients.
authors.affiliation: Departments of Biomedicine and Anesthesia, Basel University Hospital, Basel University, Basel, Switzerland.
authors.forename: Christoph
authors.initials: C
authors.lastname: Bachmann
authors.affiliation: Department of Paediatric Neurology, Neuromuscular Service, Evelina Children's Hospital, St Thomas' Hospital, London, UK.|Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King's College London, London, UK.|Randall Division of Cell and Molecular Biophysics, Muscle Signalling Section, King's College, London, UK.
authors.forename: Heinz
authors.initials: H
authors.lastname: Jungbluth
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: Dubowitz Neuromuscular Centre and MRC Centre for Neuromuscular Diseases, Institute of Child Health, London, UK.
authors.forename: Adnan Y
authors.initials: AY
authors.lastname: Manzur
authors.affiliation: Departments of Biomedicine and Anesthesia, Basel University Hospital, Basel University, 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: Departments of Biomedicine and Anesthesia, Basel University Hospital, Basel University, Basel, Switzerland.|Department of Life Sciences, General Pathology section, University of Ferrara, Ferrara, Italy.
authors.forename: Susan
authors.initials: S
authors.lastname: Treves
mesh_terms: D000818:Animals; D001706:Biopsy; D002118:Calcium / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D005260:Female; D005786:Gene Expression Regulation; D006655:Histone Deacetylases / Q000096:biosynthesis / Q000235:genetics*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology; D009154:Mutation; D020914:Myopathies, Structural, Congenital / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D054558:Protein Tyrosine Phosphatases, Non-Receptor / Q000235:genetics*; D012097:Repressor Proteins / Q000096:biosynthesis / Q000235:genetics*; D019837:Ryanodine Receptor Calcium Release Channel / Q000096:biosynthesis / Q000235:genetics*; D015027:Zebrafish
chemical_list: D035683:MicroRNAs; D012097:Repressor Proteins; D019837:Ryanodine Receptor Calcium Release Channel; D054558:Protein Tyrosine Phosphatases, Non-Receptor; C099588:myotubularin; C400300:HDAC4 protein, human; D006655:Histone Deacetylases; D002118:Calcium