Early signs of architectural and biomechanical failure in isolated myofibers and immortalized myoblasts from desmin-mutant knock-in mice

Abstract In striated muscle, desmin intermediate filaments interlink the contractile myofibrillar apparatus with mitochondria, nuclei, and the sarcolemma. The desmin network’s pivotal role in myocytes is evident since mutations in the human desmin gene cause severe myopathies and cardiomyopathies. H...

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Autores principales:	Stefanie Diermeier, Julian Iberl, Kristina Vetter, Michael Haug, Charlotte Pollmann, Barbara Reischl, Andreas Buttgereit, Sebastian Schürmann, Marina Spörrer, Wolfgang H. Goldmann, Ben Fabry, Fatiha Elhamine, Robert Stehle, Gabriele Pfitzer, Lilli Winter, Christoph S. Clemen, Harald Herrmann, Rolf Schröder, Oliver Friedrich
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/34b6157e38954bd2be2d2f1991aef0fe
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spelling	oai:doaj.org-article:34b6157e38954bd2be2d2f1991aef0fe2021-12-02T16:07:59ZEarly signs of architectural and biomechanical failure in isolated myofibers and immortalized myoblasts from desmin-mutant knock-in mice10.1038/s41598-017-01485-x2045-2322https://doaj.org/article/34b6157e38954bd2be2d2f1991aef0fe2017-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-01485-xhttps://doaj.org/toc/2045-2322Abstract In striated muscle, desmin intermediate filaments interlink the contractile myofibrillar apparatus with mitochondria, nuclei, and the sarcolemma. The desmin network’s pivotal role in myocytes is evident since mutations in the human desmin gene cause severe myopathies and cardiomyopathies. Here, we investigated skeletal muscle pathology in myofibers and myofibrils isolated from young hetero- and homozygous R349P desmin knock-in mice, which carry the orthologue of the most frequent human desmin missense mutation R350P. We demonstrate that mutant desmin alters myofibrillar cytoarchitecture, markedly disrupts the lateral sarcomere lattice and distorts myofibrillar angular axial orientation. Biomechanical assessment revealed a high predisposition to stretch-induced damage in fiber bundles of R349P mice. Notably, Ca2 +-sensitivity and passive myofibrillar tension were decreased in heterozygous fiber bundles, but increased in homozygous fiber bundles compared to wildtype mice. In a parallel approach, we generated and subsequently subjected immortalized heterozygous R349P desmin knock-in myoblasts to magnetic tweezer experiments that revealed a significantly increased sarcolemmal lateral stiffness. Our data suggest that mutated desmin already markedly impedes myocyte structure and function at pre-symptomatic stages of myofibrillar myopathies.Stefanie DiermeierJulian IberlKristina VetterMichael HaugCharlotte PollmannBarbara ReischlAndreas ButtgereitSebastian SchürmannMarina SpörrerWolfgang H. GoldmannBen FabryFatiha ElhamineRobert StehleGabriele PfitzerLilli WinterChristoph S. ClemenHarald HerrmannRolf SchröderOliver FriedrichNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-14 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Stefanie Diermeier Julian Iberl Kristina Vetter Michael Haug Charlotte Pollmann Barbara Reischl Andreas Buttgereit Sebastian Schürmann Marina Spörrer Wolfgang H. Goldmann Ben Fabry Fatiha Elhamine Robert Stehle Gabriele Pfitzer Lilli Winter Christoph S. Clemen Harald Herrmann Rolf Schröder Oliver Friedrich Early signs of architectural and biomechanical failure in isolated myofibers and immortalized myoblasts from desmin-mutant knock-in mice
description	Abstract In striated muscle, desmin intermediate filaments interlink the contractile myofibrillar apparatus with mitochondria, nuclei, and the sarcolemma. The desmin network’s pivotal role in myocytes is evident since mutations in the human desmin gene cause severe myopathies and cardiomyopathies. Here, we investigated skeletal muscle pathology in myofibers and myofibrils isolated from young hetero- and homozygous R349P desmin knock-in mice, which carry the orthologue of the most frequent human desmin missense mutation R350P. We demonstrate that mutant desmin alters myofibrillar cytoarchitecture, markedly disrupts the lateral sarcomere lattice and distorts myofibrillar angular axial orientation. Biomechanical assessment revealed a high predisposition to stretch-induced damage in fiber bundles of R349P mice. Notably, Ca2 +-sensitivity and passive myofibrillar tension were decreased in heterozygous fiber bundles, but increased in homozygous fiber bundles compared to wildtype mice. In a parallel approach, we generated and subsequently subjected immortalized heterozygous R349P desmin knock-in myoblasts to magnetic tweezer experiments that revealed a significantly increased sarcolemmal lateral stiffness. Our data suggest that mutated desmin already markedly impedes myocyte structure and function at pre-symptomatic stages of myofibrillar myopathies.
format	article
author	Stefanie Diermeier Julian Iberl Kristina Vetter Michael Haug Charlotte Pollmann Barbara Reischl Andreas Buttgereit Sebastian Schürmann Marina Spörrer Wolfgang H. Goldmann Ben Fabry Fatiha Elhamine Robert Stehle Gabriele Pfitzer Lilli Winter Christoph S. Clemen Harald Herrmann Rolf Schröder Oliver Friedrich
author_facet	Stefanie Diermeier Julian Iberl Kristina Vetter Michael Haug Charlotte Pollmann Barbara Reischl Andreas Buttgereit Sebastian Schürmann Marina Spörrer Wolfgang H. Goldmann Ben Fabry Fatiha Elhamine Robert Stehle Gabriele Pfitzer Lilli Winter Christoph S. Clemen Harald Herrmann Rolf Schröder Oliver Friedrich
author_sort	Stefanie Diermeier
title	Early signs of architectural and biomechanical failure in isolated myofibers and immortalized myoblasts from desmin-mutant knock-in mice
title_short	Early signs of architectural and biomechanical failure in isolated myofibers and immortalized myoblasts from desmin-mutant knock-in mice
title_full	Early signs of architectural and biomechanical failure in isolated myofibers and immortalized myoblasts from desmin-mutant knock-in mice
title_fullStr	Early signs of architectural and biomechanical failure in isolated myofibers and immortalized myoblasts from desmin-mutant knock-in mice
title_full_unstemmed	Early signs of architectural and biomechanical failure in isolated myofibers and immortalized myoblasts from desmin-mutant knock-in mice
title_sort	early signs of architectural and biomechanical failure in isolated myofibers and immortalized myoblasts from desmin-mutant knock-in mice
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/34b6157e38954bd2be2d2f1991aef0fe
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Early signs of architectural and biomechanical failure in isolated myofibers and immortalized myoblasts from desmin-mutant knock-in mice

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