Filamin-A-interacting protein 1 (FILIP1) is a dual compartment protein linking myofibrils and microtubules during myogenic differentiation and upon mechanical stress

• Published in: Cell and tissue research 2023-07, Vol.393 (1), p.133-147
• Main Authors: Grande, Valentina, Schuld, Julia, van der Ven, Peter F. M., Gruss, Oliver J., Fürst, Dieter O.
• Format: Article
• Language: English
• Subjects: Actin; Binding proteins; Biomedical and Life Sciences; Biomedicine; Filaments; Human Genetics; Lesions; Localization; Microtubules; Molecular Medicine; Muscle proteins; Muscles; Myofibrils; Myotubes; Nocodazole; Protein binding; Proteins; Proteomics; Regular; Regular Article; Skeletal muscle; Ventricle; Ventricular zone
• ISSN: 0302-766X; 1432-0878
• DOI: 10.1007/s00441-023-03776-4

Variations in the gene encoding filamin-A-interacting protein 1 ( FILIP1 ) were identified to be associated with a combination of neurological and muscular symptoms. While FILIP1 was shown to regulate motility of brain ventricular zone cells, a process important for corticogenesis, the function of the protein in muscle cells has been less well characterized. The expression of FILIP1 in regenerating muscle fibres predicted a role in early muscle differentiation. Here we analysed expression and localization of FILIP1 and its binding partners filamin-C (FLNc) and microtubule plus-end-binding protein EB3 in differentiating cultured myotubes and adult skeletal muscle. Prior to the development of cross-striated myofibrils, FILIP1 is associated with microtubules and colocalizes with EB3. During further myofibril maturation its localization changes, and FILIP1 localizes to myofibrillar Z-discs together with the actin-binding protein FLNc. Forced contractions of myotubes by electrical pulse stimulation (EPS) induce focal disruptions in myofibrils and translocation of both proteins from Z-discs to these lesions, suggesting a role in induction and/or repair of these structures. The immediate proximity of tyrosylated, dynamic microtubules and EB3 to lesions implies that also these play a role in these processes. This implication is supported by the fact that in nocodazole-treated myotubes that lack functional microtubules, the number of lesions induced by EPS is significantly reduced. In summary, we here show that FILIP1 is a cytolinker protein that is associated with both microtubules and actin filaments, and might play a role in the assembly of myofibrils and their stabilization upon mechanical stress to protect them from damage.