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Acta Neuropathol. 2019 Sep;138(3):477-495. doi: 10.1007/s00401-019-02034-8. Epub 2019 Jun 19.

Impairments in contractility and cytoskeletal organisation cause nuclear defects in nemaline myopathy.

Author information

1
Centre for Human and Applied Physiological Sciences, School of Basic and Medical Biosciences, Faculty of Life Sciences and Medicine, Guy's Campus, King's College London, London, SE1 1UL, UK. jacob.ross@kcl.ac.uk.
2
Centre for Human and Applied Physiological Sciences, School of Basic and Medical Biosciences, Faculty of Life Sciences and Medicine, Guy's Campus, King's College London, London, SE1 1UL, UK.
3
Neuromuscular and Rare Diseases Unit, Department of Neuroscience, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, 20122, Italy.
4
Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ, 85721, USA.
5
Division of Biosciences, University College London, Gower Street, London, WC1E 6BT, UK.
6
Randall Centre for Cell and Molecular Biophysics, School of Basic and Medical Biosciences, Faculty of Life Sciences and Medicine, Guy's Campus, King's College London, London, SE1 1UL, UK.
7
Department of Neurology, University Hospitals Leuven, Herestraat 49, 3000, Louvain, Belgium.
8
Laboratory for Muscle Diseases and Neuropathies, Department of Neurosciences, KU Leuven, Louvain, Belgium.
9
Institute of Neuropathology, RWTH Aachen University Hospital, Aachen, Germany.
10
Unità Operativa Complessa di Neurologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, Largo A. Gemelli 8, 00168, Rome, Italy.
11
Department of Paediatric Neurology, Neuromuscular Service, Evelina's Children Hospital, Guy's and St Thomas' Hospital National Health Service Foundation Trust, London, SE1 9RT, UK.
12
Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College, London, SE1 1UL, UK.
13
IRCCS Gaslini and Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, Genoa University, Genoa, Italy.
14
Copenhagen Neuromuscular Center, Rigshospitalet, University of Copenhagen, 2100, Copenhagen, Denmark.
15
Department of Neurology, Faculdade de Medicina (FMUSP), Universidade de São Paulo, São Paulo, Brazil.
16
Neuromuscular and Regenerative Medicine Unit, School of Medical Sciences, University of New South Wales, Sydney, NSW, 2052, Australia.
17
The Folkhälsan Institute of Genetics and Department of Medical and Clinical Genetics, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.

Abstract

Nemaline myopathy (NM) is a skeletal muscle disorder caused by mutations in genes that are generally involved in muscle contraction, in particular those related to the structure and/or regulation of the thin filament. Many pathogenic aspects of this disease remain largely unclear. Here, we report novel pathological defects in skeletal muscle fibres of mouse models and patients with NM: irregular spacing and morphology of nuclei; disrupted nuclear envelope; altered chromatin arrangement; and disorganisation of the cortical cytoskeleton. Impairments in contractility are the primary cause of these nuclear defects. We also establish the role of microtubule organisation in determining nuclear morphology, a phenomenon which is likely to contribute to nuclear alterations in this disease. Our results overlap with findings in diseases caused directly by mutations in nuclear envelope or cytoskeletal proteins. Given the important role of nuclear shape and envelope in regulating gene expression, and the cytoskeleton in maintaining muscle fibre integrity, our findings are likely to explain some of the hallmarks of NM, including contractile filament disarray, altered mechanical properties and broad transcriptional alterations.

KEYWORDS:

Actin; Lamin; Microtubules; Nemaline myopathy; Nuclear envelope; Skeletal muscle

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