Universität zu Köln

Diermeier, Stefanie, Iberl, Julian, Vetter, Kristina, Haug, Michael, Pollmann, Charlotte, Reischl, Barbara, Buttgereit, Andreas, Schuermann, Sebastian, Spoerrer, Marina, Goldmann, Wolfgang H., Fabry, Ben ORCID: 0000-0003-1737-0465, Elhamine, Fatiha, Stehle, Robert, Pfitzer, Gabriele, Winter, Lilli ORCID: 0000-0002-6368-1160, Clemen, Christoph S., Herrmann, Harald, Schroeder, Rolf and Friedrich, Oliver ORCID: 0000-0003-2238-2049 (2017). Early signs of architectural and biomechanical failure in isolated myofibers and immortalized myoblasts from desmin-mutant knock-in mice. Sci Rep, 7. LONDON: NATURE PUBLISHING GROUP. ISSN 2045-2322

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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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Diermeier, Stefanie UNSPECIFIED UNSPECIFIED UNSPECIFIED Iberl, Julian UNSPECIFIED UNSPECIFIED UNSPECIFIED Vetter, Kristina UNSPECIFIED UNSPECIFIED UNSPECIFIED Haug, Michael UNSPECIFIED UNSPECIFIED UNSPECIFIED Pollmann, Charlotte UNSPECIFIED UNSPECIFIED UNSPECIFIED Reischl, Barbara UNSPECIFIED UNSPECIFIED UNSPECIFIED Buttgereit, Andreas UNSPECIFIED UNSPECIFIED UNSPECIFIED Schuermann, Sebastian UNSPECIFIED UNSPECIFIED UNSPECIFIED Spoerrer, Marina UNSPECIFIED UNSPECIFIED UNSPECIFIED Goldmann, Wolfgang H. UNSPECIFIED UNSPECIFIED UNSPECIFIED Fabry, Ben UNSPECIFIED orcid.org/0000-0003-1737-0465 UNSPECIFIED Elhamine, Fatiha UNSPECIFIED UNSPECIFIED UNSPECIFIED Stehle, Robert UNSPECIFIED UNSPECIFIED UNSPECIFIED Pfitzer, Gabriele UNSPECIFIED UNSPECIFIED UNSPECIFIED Winter, Lilli UNSPECIFIED orcid.org/0000-0002-6368-1160 UNSPECIFIED Clemen, Christoph S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Herrmann, Harald UNSPECIFIED UNSPECIFIED UNSPECIFIED Schroeder, Rolf UNSPECIFIED UNSPECIFIED UNSPECIFIED Friedrich, Oliver UNSPECIFIED orcid.org/0000-0003-2238-2049 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-231361
DOI:	10.1038/s41598-017-01485-x
Journal or Publication Title:	Sci Rep
Volume:	7
Date:	2017
Publisher:	NATURE PUBLISHING GROUP
Place of Publication:	LONDON
ISSN:	2045-2322
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language REGULATORY LIGHT-CHAINS; SKELETAL-MUSCLE; INTERMEDIATE-FILAMENTS; 2ND-HARMONIC GENERATION; MUSCULAR-DYSTROPHY; STRIATED-MUSCLE; NUCLEAR SHAPE; MYOPATHY; MUTATION; MOUSE Multiple languages Multidisciplinary Sciences Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/23136