Dystrophy-associated caveolin-3 mutations reveal that caveolae couple IL6/STAT3 signaling with mechanosensing in human muscle cells

Melissa Dewulf, Darius Vasco Köster, Bidisha Sinha, Christine Viaris de Lesegno, Valérie Chambon, Anne Bigot, Mona Bensalah, Elisa Negroni, Nicolas Tardif, Joanna Podkalicka, Ludger Johannes, Pierre Nassoy, Gillian Butler-Browne, Christophe Lamaze () and Cedric M. Blouin ()
Additional contact information
Melissa Dewulf: Institut Curie – Centre de Recherche, PSL Research University, CNRS UMR3666, INSERM U1143
Darius Vasco Köster: University of Warwick
Bidisha Sinha: Indian Institute of Science Education and Research (IISER) Kolkata
Christine Viaris de Lesegno: Institut Curie – Centre de Recherche, PSL Research University, CNRS UMR3666, INSERM U1143
Valérie Chambon: Institut Curie – Centre de Recherche, PSL Research University, CNRS UMR3666, INSERM U1143
Anne Bigot: Sorbonne Université, INSERM, UMRS974
Mona Bensalah: Sorbonne Université, INSERM, UMRS974
Elisa Negroni: Sorbonne Université, INSERM, UMRS974
Nicolas Tardif: Institut Curie – Centre de Recherche, PSL Research University, CNRS UMR3666, INSERM U1143
Joanna Podkalicka: Institut Curie – Centre de Recherche, PSL Research University, CNRS UMR3666, INSERM U1143
Ludger Johannes: Institut Curie – Centre de Recherche, PSL Research University, CNRS UMR3666, INSERM U1143
Pierre Nassoy: IOA, Institut d’Optique Graduate School, Université de Bordeaux
Gillian Butler-Browne: Sorbonne Université, INSERM, UMRS974
Christophe Lamaze: Institut Curie – Centre de Recherche, PSL Research University, CNRS UMR3666, INSERM U1143
Cedric M. Blouin: Institut Curie – Centre de Recherche, PSL Research University, CNRS UMR3666, INSERM U1143

Nature Communications, 2019, vol. 10, issue 1, 1-13

Abstract: Abstract Caveolin-3 is the major structural protein of caveolae in muscle. Mutations in the CAV3 gene cause different types of myopathies with altered membrane integrity and repair, expression of muscle proteins, and regulation of signaling pathways. We show here that myotubes from patients bearing the CAV3 P28L and R26Q mutations present a dramatic decrease of caveolae at the plasma membrane, resulting in abnormal response to mechanical stress. Mutant myotubes are unable to buffer the increase in membrane tension induced by mechanical stress. This results in impaired regulation of the IL6/STAT3 signaling pathway leading to its constitutive hyperactivation and increased expression of muscle genes. These defects are fully reversed by reassembling functional caveolae through expression of caveolin-3. Our study reveals that under mechanical stress the regulation of mechanoprotection by caveolae is directly coupled with the regulation of IL6/STAT3 signaling in muscle cells and that this regulation is absent in Cav3-associated dystrophic patients.

Date: 2019
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DOI: 10.1038/s41467-019-09405-5

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