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

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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 , Zanoteli , E , Hardeman , E C , Wallgren-Pettersson , C & Ochala , J 2019 , ' Impairments in contractility and cytoskeletal organisation cause nuclear defects in nemaline myopathy ' , Acta Neuropathologica , vol. 138 , no. 3 , pp. 477-495 . https://doi.org/10.1007/s00401-019-02034-8

Title: Impairments in contractility and cytoskeletal organisation cause nuclear defects in nemaline myopathy
Author: Ross, Jacob A.; Levy, Yotam; Ripolone, Michela; Kolb, Justin S.; Turmaine, Mark; Holt, Mark; Lindqvist, Johan; Claeys, Kristl G.; Weis, Joachim; Monforte, Mauro; Tasca, Giorgio; Moggio, Maurizio; Figeac, Nicolas; Zammit, Peter S.; Jungbluth, Heinz; Fiorillo, Chiara; Vissing, John; Witting, Nanna; Granzier, Henk; Zanoteli, Edmar; Hardeman, Edna C.; Wallgren-Pettersson, Carina; Ochala, Julien
Contributor: University of Helsinki, Medicum
Date: 2019-09
Language: eng
Number of pages: 19
Belongs to series: Acta Neuropathologica
ISSN: 0001-6322
URI: http://hdl.handle.net/10138/305081
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.
Subject: Skeletal muscle
Nemaline myopathy
Microtubules
Actin
Lamin
Nuclear envelope
DREIFUSS MUSCULAR-DYSTROPHY
MYONUCLEAR DOMAIN SIZE
THIN FILAMENT LENGTH
SKELETAL-MUSCLE
ACTIN
ENVELOPE
TRANSCRIPTION
MUTATIONS
DYSFUNCTION
ANCHORAGE
3112 Neurosciences
3124 Neurology and psychiatry
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