title: Myofibrillar instability exacerbated by acute exercise in filaminopathy.
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.affiliation: Institute of Neuropathology.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Chevessier
authors.affiliation: Department of Molecular Cell Biology, Institute for Cell Biology, University of Bonn, Bonn, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Schuld
authors.affiliation: Department of Molecular Cell Biology, Institute for Cell Biology, University of Bonn, Bonn, Germany.
authors.forename: Zacharias
authors.initials: Z
authors.lastname: Orfanos
authors.affiliation: Department for Experimental Therapy, Preclinical Experimental Animal Center and.
authors.forename: Anne-C
authors.initials: AC
authors.lastname: Plank
authors.affiliation: Institute of Neuropathology.
authors.forename: Lucie
authors.initials: L
authors.lastname: Wolf
authors.affiliation: Department of Neurology, Neuromuscular Center Ruhrgebiet, University Hospital Bergmannsheil, Department of Functional Proteomics, Medizinisches Proteom-Center and.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Maerkens
authors.affiliation: Department of Cardiovascular Physiology, Ruhr-University Bochum, Bochum, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Unger
authors.affiliation: Department of Ophthalmology, University Hospital Erlangen, Erlangen, Germany.
authors.forename: Ursula
authors.initials: U
authors.lastname: Schlötzer-Schrehardt
authors.affiliation: Department of Neurology, Neuromuscular Center Ruhrgebiet, University Hospital Bergmannsheil.
authors.forename: Rudolf A
authors.initials: RA
authors.lastname: Kley
authors.affiliation: Department for Experimental Therapy, Preclinical Experimental Animal Center and.
authors.forename: Stephan
authors.initials: S
authors.lastname: Von Hörsten
authors.affiliation: Department of Functional Proteomics, Medizinisches Proteom-Center and.
authors.forename: Katrin
authors.initials: K
authors.lastname: Marcus
authors.affiliation: Department of Cardiovascular Physiology, Ruhr-University Bochum, Bochum, Germany.
authors.forename: Wolfgang A
authors.initials: WA
authors.lastname: Linke
authors.affiliation: Department of Neurology, Neuromuscular Center Ruhrgebiet, University Hospital Bergmannsheil.
authors.forename: Matthias
authors.initials: M
authors.lastname: Vorgerd
authors.affiliation: Department of Molecular Cell Biology, Institute for Cell Biology, University of Bonn, Bonn, Germany.
authors.forename: Peter F M
authors.initials: PF
authors.lastname: van der Ven
authors.affiliation: Department of Molecular Cell Biology, Institute for Cell Biology, University of Bonn, Bonn, Germany, dfuerst@uni-bonn.de rolf.schroeder@uk-erlangen.de.
authors.forename: Dieter O
authors.initials: DO
authors.lastname: Fürst
authors.affiliation: Institute of Neuropathology, dfuerst@uni-bonn.de rolf.schroeder@uk-erlangen.de.
authors.forename: Rolf
authors.initials: R
authors.lastname: Schröder
mesh_terms: D000818:Animals; D064448:Filamins / Q000235:genetics; D005838:Genotype; D051379:Mice; D008854:Microscopy, Electron; D018482:Muscle, Skeletal / Q000473:pathology*; D009135:Muscular Diseases / Q000235:genetics / Q000473:pathology; D009136:Muscular Dystrophies / Q000235:genetics; D009210:Myofibrils / Q000235:genetics / Q000473:pathology*; D010641:Phenotype
chemical_list: D064448:Filamins