Myofibrillar instability exacerbated by acute exercise in filaminopathy

Chevessier F, Schuld J, Orfanos Z, Plank AC, Wolf L, Maerkens A, Unger A, Schlötzer-Schrehardt U, Kley RA, von Hörsten S, Marcus K, Linke WA, Vorgerd M, Van Der Ven PFM, Fuerst DO, Schröder R (2015)

Publication Type: Journal article

Publication year: 2015

Journal

Human Molecular Genetics Oxford University Press (OUP): Policy B - Oxford Open Option B

Book Volume: 24

Pages Range: 7207-20

Journal Issue: 25

DOI: 10.1093/hmg/ddv421

Abstract

Filamin C (FLNC) mutations in humans cause myofibrillar myopathy (MFM) and cardiomyopathy, characterized by protein aggregation and myofibrillar degeneration. We generated the first patient-mimicking knock-in mouse harbouring the most common disease-causing filamin C mutation (p.W2710X). These heterozygous mice developed muscle weakness and myofibrillar instability, with formation of filamin C- and Xin-positive lesions streaming between Z-discs. These lesions, which are distinct from the classical MFM protein aggregates by their morphology and filamentous appearance, were greatly increased in number upon acute physical exercise in the mice. This pathology suggests that mutant filamin influences the mechanical stability of myofibrillar Z-discs, explaining the muscle weakness in mice and humans. Re-evaluation of biopsies from MFM-filaminopathy patients with different FLNC mutations revealed a similar, previously unreported lesion pathology, in addition to the classical protein aggregates, and suggested that structures previously interpreted as aggregates may be in part sarcomeric lesions. We postulate that these lesions define preclinical disease stages, preceding the formation of protein aggregates.

Authors with CRIS profile

Anne-Christine Plank Professur für Experimentelle Biomedizin Ursula Schlötzer-Schrehardt Medizinische Fakultät Stephan von Hörsten Professur für Experimentelle Biomedizin Rolf Schröder Professur für Neuropathologie

Involved external institutions

Rheinische Friedrich-Wilhelms-Universität Bonn DE Germany (DE) Ruhr-Universität Bochum (RUB) DE Germany (DE)

How to cite

APA:

Chevessier, F., Schuld, J., Orfanos, Z., Plank, A.-C., Wolf, L., Maerkens, A.,... Schröder, R. (2015). Myofibrillar instability exacerbated by acute exercise in filaminopathy. Human Molecular Genetics, 24(25), 7207-20. https://doi.org/10.1093/hmg/ddv421

MLA:

Chevessier, Frederic, et al. "Myofibrillar instability exacerbated by acute exercise in filaminopathy." Human Molecular Genetics 24.25 (2015): 7207-20.

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