Impairments in contractility and cytoskeletal organisation cause nuclear defects in nemaline myopathy
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Impairments in contractility and cytoskeletal organisation cause nuclear defects in nemaline myopathy. / 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.
I: Acta Neuropathologica, Bind 138, Nr. 3, 2019, s. 477-495.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › fagfællebedømt
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TY - JOUR
T1 - Impairments in contractility and cytoskeletal organisation cause nuclear defects in nemaline myopathy
AU - Ross, Jacob A.
AU - Levy, Yotam
AU - Ripolone, Michela
AU - Kolb, Justin S.
AU - Turmaine, Mark
AU - Holt, Mark
AU - Lindqvist, Johan
AU - Claeys, Kristl G.
AU - Weis, Joachim
AU - Monforte, Mauro
AU - Tasca, Giorgio
AU - Moggio, Maurizio
AU - Figeac, Nicolas
AU - Zammit, Peter S.
AU - Jungbluth, Heinz
AU - Fiorillo, Chiara
AU - Vissing, John
AU - Witting, Nanna
AU - Granzier, Henk
AU - Zanoteli, Edmar
AU - Hardeman, Edna C.
AU - Wallgren-Pettersson, Carina
AU - Ochala, Julien
PY - 2019
Y1 - 2019
N2 - 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.
AB - 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.
KW - Actin
KW - Lamin
KW - Microtubules
KW - Nemaline myopathy
KW - Nuclear envelope
KW - Skeletal muscle
U2 - 10.1007/s00401-019-02034-8
DO - 10.1007/s00401-019-02034-8
M3 - Journal article
C2 - 31218456
AN - SCOPUS:85067690372
VL - 138
SP - 477
EP - 495
JO - Acta Neuropathologica
JF - Acta Neuropathologica
SN - 0001-6322
IS - 3
ER -
ID: 226870940