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

Lookup NU author(s): Professor Giorgio TascaORCiD



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


© 2019, The Author(s).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.

Publication metadata

Author(s): Ross JA, Levy Y, Ripolone M, Kolb JS, Turmaine M, Holt M, Lindqvist J, Claeys KG, Weis J, Monforte M, Tasca G, Moggio M, Figeac N, Zammit PS, Jungbluth H, Fiorillo C, Vissing J, Witting N, Granzier H, Zanoteli E, Hardeman EC, Wallgren-Pettersson C, Ochala J

Publication type: Article

Publication status: Published

Journal: Acta Neuropathologica

Year: 2019

Volume: 138

Issue: 3

Pages: 477-495

Print publication date: 01/09/2019

Online publication date: 19/06/2019

Acceptance date: 05/06/2019

Date deposited: 01/03/2023

ISSN (print): 0001-6322

ISSN (electronic): 1432-0533

Publisher: Springer Verlag


DOI: 10.1007/s00401-019-02034-8

PubMed id: 31218456


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