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bioRxiv · 10.1101/2021.08.05.455167

Dystrophin modulates focal adhesion tension and YAP-mediated mechanotransduction

Ramirez, M. P.·Anderson, M. J.·Sundby, L. J.·Hagerty, A. R.·Wenthe, S. J.·Ervasti, J. M.·Gordon, W. R.
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Abstract

Dystrophin is an essential muscle protein that contributes to cell membrane stability by linking the actin cytoskeleton to the extracellular matrix. The absence or impaired function of dystrophin causes muscular dystrophy. Focal adhesions are mechanosensitive adhesion complexes that also connect the cytoskeleton to the extracellular matrix. However, the interplay between dystrophin and focal adhesion force transmission has not been investigated. Using a bioluminescent tension sensor, we measured focal adhesion tension in transgenic C2C12 myoblasts expressing wild type (WT) dystrophin, a non-pathogenic SNP (I232M), or two missense mutations associated with Duchenne (L54R), or Becker muscular dystrophy (L172H). We found that myoblasts expressing WT or nonpathogenic I232M dystrophin showed increased focal adhesion tension compared to non-transgenic myoblasts, while myoblasts expressing L54R or L172H dystrophin presented with decreased focal adhesion tension. Moreover, myoblasts expressing L54R or L172H dystrophin showed decreased YAP activation and exhibited slower and less directional migration compared to cells expressing WT or I232M dystrophin. Our results suggest that disease-causing missense mutations in dystrophin may disrupt a cellular tension sensing pathway in dystrophic skeletal muscle.

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Ramirez, M. P., Anderson, M. J., Sundby, L. J., Hagerty, A. R., Wenthe, S. J., Ervasti, J. M., Gordon, W. R.. 2021-08-06. Dystrophin modulates focal adhesion tension and YAP-mediated mechanotransduction. https://doi.org/10.1101/2021.08.05.455167

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