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Hum Mol Genet. 2015 Dec 20;24(25):7207-20. doi: 10.1093/hmg/ddv421. Epub 2015 Oct 15.

Myofibrillar instability exacerbated by acute exercise in filaminopathy.

Author information

1
Institute of Neuropathology.
2
Department of Molecular Cell Biology, Institute for Cell Biology, University of Bonn, Bonn, Germany.
3
Department for Experimental Therapy, Preclinical Experimental Animal Center and.
4
Department of Neurology, Neuromuscular Center Ruhrgebiet, University Hospital Bergmannsheil, Department of Functional Proteomics, Medizinisches Proteom-Center and.
5
Department of Cardiovascular Physiology, Ruhr-University Bochum, Bochum, Germany.
6
Department of Ophthalmology, University Hospital Erlangen, Erlangen, Germany.
7
Department of Neurology, Neuromuscular Center Ruhrgebiet, University Hospital Bergmannsheil.
8
Department of Functional Proteomics, Medizinisches Proteom-Center and.
9
Department of Molecular Cell Biology, Institute for Cell Biology, University of Bonn, Bonn, Germany, dfuerst@uni-bonn.de rolf.schroeder@uk-erlangen.de.
10
Institute of Neuropathology, dfuerst@uni-bonn.de rolf.schroeder@uk-erlangen.de.

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.

PMID:
26472074
DOI:
10.1093/hmg/ddv421
[Indexed for MEDLINE]

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