ZFIN ID: ZDB-PUB-160522-8
Filamin C is a highly dynamic protein associated with fast repair of myofibrillar microdamage
Leber, Y., Ruparelia, A.A., Kirfel, G., van der Ven, P.F., Hoffmann, B., Merkel, R., Bryson-Richardson, R.J., Fürst, D.O.
Date: 2016
Source: Human molecular genetics   25(13): 2776-2788 (Journal)
Registered Authors: Bryson-Richardson, Robert, Ruparelia, Avnika
Keywords: none
MeSH Terms:
  • Actins/metabolism
  • Animals
  • Cell Culture Techniques
  • Cytoskeletal Proteins/genetics
  • DNA-Binding Proteins/genetics
  • Filamins/genetics*
  • Filamins/metabolism*
  • Filamins/physiology
  • Humans
  • Mice
  • Muscle, Skeletal/metabolism
  • Muscular Diseases/genetics
  • Mutation
  • Myocardium/metabolism
  • Myocytes, Cardiac/metabolism
  • Myofibrils/pathology*
  • Nuclear Proteins/genetics
  • Protein Binding
PubMed: 27206985 Full text @ Hum. Mol. Genet.
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 hours, 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.