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 Zanoteli; Edna C. Hardeman; Carina Wallgren-Pettersson; Julien Ochala

doi:10.1007/s00401-019-02034-8

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

^*Corresponding author for this work

Department of Clinical Medicine

4 Citations (Scopus)

12 Downloads (Pure)

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 language	English
Journal	Acta Neuropathologica
Volume	138
Issue number	3
Pages (from-to)	477-495
Number of pages	19
ISSN	0001-6322
DOIs	https://doi.org/10.1007/s00401-019-02034-8
Publication status	Published - 2019

Keywords

Actin
Lamin
Microtubules
Nemaline myopathy
Nuclear envelope
Skeletal muscle

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Impairments in contractility and cytoskeletal organisation cause nuclear defects in nemaline myopathyFinal published version, 9.96 MBLicence: CC BY

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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

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 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

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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",

year = "2019",

doi = "10.1007/s00401-019-02034-8",

language = "English",

volume = "138",

pages = "477--495",

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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

SN - 0001-6322

VL - 138

SP - 477

EP - 495

JO - Acta Neuropathologica

JF - Acta Neuropathologica

IS - 3

ER -

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

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