Filamin C Modulates Cellular Mechanoresponse Through Focal Adhesion Turnover and Actin Stabilization

Area of Science:

• Cell Biology
• Muscle Development
• Mechanotransduction

Background:

• Filamin C (FLNC) is crucial for cytoskeletal integrity and mechanosensing.
• Dysfunctional mechanosensitive pathways, including YAP/TAZ and β-catenin, are implicated in various muscle disorders.
• The precise role of FLNC in regulating these pathways remains unclear.

Purpose of the Study:

• To investigate the mechanistic basis of impaired YAP/TAZ and β-catenin signaling in filamin C-deficient cells.
• To elucidate the role of filamin C in regulating actin cytoskeleton organization, focal adhesion dynamics, and mechanotransduction.

Main Methods:

• Utilized filamin C knockout (FlncKO) C2C12 myoblasts.
• Analyzed transcriptomic profiles, actin organization, and focal adhesion structures.
• Employed pharmacological inhibitors (Verteporfin, Jasplakinolide, (-)Blebbistatin, Y-27632) to probe signaling pathways.

Main Results:

• Filamin C deficiency led to increased F/G-actin ratio, enlarged focal adhesions, and reduced nuclear YAP/TAZ and β-catenin.
• Actin stabilization (Jasplakinolide) rescued YAP/TAZ signaling in FlncKO cells.
• ROCK inhibition (Y-27632) promoted focal adhesion disassembly and restored β-catenin localization specifically in FlncKO cells.

Conclusions:

• Filamin C is essential for proper focal adhesion turnover and actomyosin complex stabilization in C2C12 muscle cells.
• FLNC deficiency compromises YAP/TAZ and β-catenin mechanotransduction, impacting muscle cell differentiation at the myoblast stage.
• Targeting aberrant focal adhesion dynamics may offer therapeutic strategies for FLNC-related myopathies.