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@ARTICLE{Leber:837684,
author = {Leber, Yvonne and Ruparelia, Avnika A. and Kirfel, Gregor
and van der Ven, Peter F. M. and Hoffmann, Bernd and Merkel,
Rudolf and Bryson-Richardson, Robert J. and Fürst, Dieter
O.},
title = {{F}ilamin {C} is a highly dynamic protein associated with
fast repair of myofibrillar microdamage},
journal = {Human molecular genetics},
volume = {25},
number = {13},
issn = {1460-2083},
address = {Oxford},
publisher = {Oxford Univ. Press},
reportid = {FZJ-2017-06546},
pages = {2776-2788},
year = {2016},
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.},
cin = {ICS-7},
ddc = {570},
cid = {I:(DE-Juel1)ICS-7-20110106},
pnm = {552 - Engineering Cell Function (POF3-552)},
pid = {G:(DE-HGF)POF3-552},
typ = {PUB:(DE-HGF)16},
UT = {WOS:000393064400013},
pubmed = {pmid:27206985},
doi = {10.1093/hmg/ddw135},
url = {https://juser.fz-juelich.de/record/837684},
}