title: Filamin C is a highly dynamic protein associated with fast repair of myofibrillar microdamage.
abstract: Filamin c (FLNc) is a large dimeric actin-binding protein located at premyofibrils, myofibrillar Z-discs and myofibrillar attachment sites of striated muscle cells, where it is involved in mechanical stabilization, mechanosensation and intracellular signaling. Mutations in the gene encoding FLNc give rise to skeletal muscle diseases and cardiomyopathies. Here, we demonstrate by fluorescence recovery after photobleaching that a large fraction of FLNc is highly mobile in cultured neonatal mouse cardiomyocytes and in cardiac and skeletal muscles of live transgenic zebrafish embryos. Analysis of cardiomyocytes from Xirp1 and Xirp2 deficient animals indicates that both Xin actin-binding repeat-containing proteins stabilize FLNc selectively in premyofibrils. Using a novel assay to analyze myofibrillar microdamage and subsequent repair in cultured contracting cardiomyocytes by live cell imaging, we demonstrate that repair of damaged myofibrils is achieved within only 4 h, even in the absence of de novo protein synthesis. FLNc is immediately recruited to these sarcomeric lesions together with its binding partner aciculin and precedes detectable assembly of filamentous actin and recruitment of other myofibrillar proteins. These data disclose an unprecedented degree of flexibility of the almost crystalline contractile machinery and imply FLNc as a dynamic signaling hub, rather than a primarily structural protein. Our myofibrillar damage/repair model illustrates how (cardio)myocytes are kept functional in their mechanically and metabolically strained environment. Our results help to better understand the pathomechanisms and pathophysiology of early stages of FLNc-related myofibrillar myopathy and skeletal and cardiac diseases preceding pathological protein aggregation.
authors.affiliation: Department of Molecular Cell Biology, Institute for Cell Biology, University of Bonn, D53121 Bonn, Germany.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Leber
authors.affiliation: School of Biological Sciences, Monash University, Melbourne, Victoria 3800, Australia.
authors.forename: Avnika A
authors.initials: AA
authors.lastname: Ruparelia
authors.affiliation: Department of Molecular Cell Biology, Institute for Cell Biology, University of Bonn, D53121 Bonn, Germany.
authors.forename: Gregor
authors.initials: G
authors.lastname: Kirfel
authors.affiliation: Department of Molecular Cell Biology, Institute for Cell Biology, University of Bonn, D53121 Bonn, Germany.
authors.forename: Peter F M
authors.initials: PF
authors.lastname: van der Ven
authors.affiliation: Department of Biomechanics (ICS-7), Institute of Complex Systems, Forschungszentrum Jülich, D52428 Jülich, Germany and.
authors.forename: Bernd
authors.initials: B
authors.lastname: Hoffmann
authors.affiliation: Department of Biomechanics (ICS-7), Institute of Complex Systems, Forschungszentrum Jülich, D52428 Jülich, Germany and.|Department of Biomechanics, Institute for Physical and Theoretical Chemistry, University of Bonn, D53115 Bonn, Germany.
authors.forename: Rudolf
authors.initials: R
authors.lastname: Merkel
authors.affiliation: School of Biological Sciences, Monash University, Melbourne, Victoria 3800, Australia.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Bryson-Richardson
authors.affiliation: Department of Molecular Cell Biology, Institute for Cell Biology, University of Bonn, D53121 Bonn, Germany dfuerst@uni-bonn.de.
authors.forename: Dieter O
authors.initials: DO
authors.lastname: Fürst
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D018929:Cell Culture Techniques; D003598:Cytoskeletal Proteins / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D064448:Filamins / Q000235:genetics* / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D051379:Mice; D018482:Muscle, Skeletal / Q000378:metabolism; D009135:Muscular Diseases / Q000235:genetics; D009154:Mutation; D009206:Myocardium / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism; D009210:Myofibrils / Q000473:pathology*; D009687:Nuclear Proteins / Q000235:genetics; D011485:Protein Binding
chemical_list: D000199:Actins; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D064448:Filamins; D009687:Nuclear Proteins