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

Jacob A Ross, Yotam Levy, Michela Ripolone, Justin S Kolb, Mark Turmaine, Mark Holt, Johan Lindqvist, Kristl G Claeys, Joachim Weis, Mauro Monforte, Giorgio Tasca, Maurizio Moggio, Nicolas Figeac, Peter S Zammit, Heinz Jungbluth, Chiara Fiorillo, John Vissing, Nanna Witting, Henk Granzier, Edmar ZanoteliEdna C Hardeman, Carina Wallgren-Pettersson, Julien Ochala

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)477-495
Number of pages19
JournalActa Neuropathologica
Volume138
Issue number3
DOIs
Publication statusPublished - Sep 2019

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    Ross, J. A., Levy, Y., Ripolone, M., Kolb, J. S., Turmaine, M., Holt, M., Lindqvist, J., Claeys, K. G., Weis, J., Monforte, M., Tasca, G., Moggio, M., Figeac, N., Zammit, P. S., Jungbluth, H., Fiorillo, C., Vissing, J., Witting, N., Granzier, H., ... Ochala, J. (2019). Impairments in contractility and cytoskeletal organisation cause nuclear defects in nemaline myopathy. Acta Neuropathologica, 138(3), 477-495. https://doi.org/10.1007/s00401-019-02034-8