@article{a852b30da23848c19f12a34326909fe0,
title = "Impairments in contractility and cytoskeletal organisation cause nuclear defects in nemaline myopathy",
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",
author = "Ross, {Jacob A.} and Yotam Levy and Michela Ripolone and Kolb, {Justin S.} and Mark Turmaine and Mark Holt and Johan Lindqvist and Claeys, {Kristl G.} and Joachim Weis and Mauro Monforte and Giorgio Tasca and Maurizio Moggio and Nicolas Figeac and Zammit, {Peter S.} and Heinz Jungbluth and Chiara Fiorillo and John Vissing and Nanna Witting and Henk Granzier and Edmar Zanoteli and Hardeman, {Edna C.} and Carina Wallgren-Pettersson and Julien Ochala",
note = "Funding Information: Acknowledgements We thank Prof Caroline Sewry for providing an electron microscopy image and for her invaluable guidance with the interpretation of the data and preparation of the manuscript. We thank Drs Wenhua Liu and Evelyn Ralston (National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, MD, USA) for providing the microtubule directionality (TeDT) tool. We also thank the Nikon Imaging Centre at King{\textquoteright}s College London for the provision of equipment for, and assistance with confocal imaging. This work was generously funded by the Medical Research Council, UK (MR/ N002768/1), and the National Institute of Arthritis and Musculoskeletal and Skin Diseases, USA (R01AR053897). Funding Information: We thank Prof Caroline Sewry for providing an electron microscopy image and for her invaluable guidance with the interpretation of the data and preparation of the manuscript. We thank Drs Wenhua Liu and Evelyn Ralston (National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, MD, USA) for providing the microtubule directionality (TeDT) tool. We also thank the Nikon Imaging Centre at King?s College London for the provision of equipment for, and assistance with confocal imaging. This work was generously funded by the Medical Research Council, UK (MR/N002768/1), and the National Institute of Arthritis and Musculoskeletal and Skin Diseases, USA (R01AR053897). Publisher Copyright: {\textcopyright} 2019, The Author(s).",
year = "2019",
month = sep,
day = "1",
doi = "10.1007/s00401-019-02034-8",
language = "English (US)",
volume = "138",
pages = "477--495",
journal = "Acta Neuropathologica",
issn = "0001-6322",
publisher = "Springer Verlag",
number = "3",
}