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Lack of functional caveolae in Cav3 mutated human dystrophic myotubes results in deficient mechanoprotection and IL6/STAT3 mechanosignaling

Melissa Dewulf, Darius Köster, View ORCID ProfileBidisha Sinha, View ORCID ProfileChristine Viaris de Lesegno, Valérie Chambon, View ORCID ProfileAnne Bigot, Nicolas Tardif, View ORCID ProfileLudger Johannes, View ORCID ProfilePierre Nassoy, View ORCID ProfileGillian Butler-Browne, View ORCID ProfileChristophe Lamaze, View ORCID ProfileCedric M. Blouin
doi: https://doi.org/10.1101/281113
Melissa Dewulf
1Institut Curie – Centre de recherche, PSL Research University, Membrane dynamics and mechanics of intracellular signaling laboratory, CNRS UMR3666, INSERM U1143, Paris, France.
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Darius Köster
2Centre for mechanochemical cell biology, University of Warwick, Coventry, United Kingdom.
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Bidisha Sinha
3Department of Biological Sciences, Indian Institute of Science Education and Research (IISER) Kolkata, Mohanpur, West Bengal, India.
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Christine Viaris de Lesegno
1Institut Curie – Centre de recherche, PSL Research University, Membrane dynamics and mechanics of intracellular signaling laboratory, CNRS UMR3666, INSERM U1143, Paris, France.
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Valérie Chambon
4Institut Curie – centre de recherche, PSL Research University, Endocytic trafficking and intracellular delivery laboratory, CNRS UMR3666, INSERM U1143, Paris, France.
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Anne Bigot
5Institut de Myologie, Sorbonne Universités, UPMC Université Paris 06, Thérapie des muscles striés laboratory, INSERM UMRS974, CNRS FRE3617, Paris, France.
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Nicolas Tardif
1Institut Curie – Centre de recherche, PSL Research University, Membrane dynamics and mechanics of intracellular signaling laboratory, CNRS UMR3666, INSERM U1143, Paris, France.
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Ludger Johannes
4Institut Curie – centre de recherche, PSL Research University, Endocytic trafficking and intracellular delivery laboratory, CNRS UMR3666, INSERM U1143, Paris, France.
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Pierre Nassoy
6LP2N, CNRS UMR 5298, IOA, Institut d’Optique Graduate School, Université de Bordeaux, Talence, France.
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Gillian Butler-Browne
5Institut de Myologie, Sorbonne Universités, UPMC Université Paris 06, Thérapie des muscles striés laboratory, INSERM UMRS974, CNRS FRE3617, Paris, France.
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Christophe Lamaze
1Institut Curie – Centre de recherche, PSL Research University, Membrane dynamics and mechanics of intracellular signaling laboratory, CNRS UMR3666, INSERM U1143, Paris, France.
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  • For correspondence: christophe.lamaze@curie.fr cedric.blouin@curie.fr
Cedric M. Blouin
1Institut Curie – Centre de recherche, PSL Research University, Membrane dynamics and mechanics of intracellular signaling laboratory, CNRS UMR3666, INSERM U1143, Paris, France.
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  • For correspondence: christophe.lamaze@curie.fr cedric.blouin@curie.fr
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Abstract

Caveolin-3 is the major structural protein of caveolae in muscle cells. Mutations in the CAV3 gene cause different type of muscle disorders mostly characterized by defects in membrane integrity and repair, deregulation in the expression of various muscle proteins and deregulation of several muscle associated signaling pathways. We show here that myotubes derived from patients bearing the CAV3 P28L and R26Q mutations present a lack of functional caveolae at the plasma membrane which results in an abnormal mechanoresponse. Mutant myotubes can no longer buffer the increase of membrane tension induced by mechanical stress and present an hyperactivation of the IL6/STAT3 signaling pathway at rest and under mechanical stress. The impaired mechanical regulation of the IL6/STAT3 signaling pathway by caveolae leads to chronic activation and a higher expression of muscle specific genes. These defects could be reversed by reassembling a pool of functional caveolae through expression of wild type Cav3. Our findings bring more mechanistic insight into human Cav3 associated muscle disorders and show a general defect in the mechanoresponse of CAV3 P28L and R26Q myotubes.

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Posted March 20, 2018.
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Lack of functional caveolae in Cav3 mutated human dystrophic myotubes results in deficient mechanoprotection and IL6/STAT3 mechanosignaling
Melissa Dewulf, Darius Köster, Bidisha Sinha, Christine Viaris de Lesegno, Valérie Chambon, Anne Bigot, Nicolas Tardif, Ludger Johannes, Pierre Nassoy, Gillian Butler-Browne, Christophe Lamaze, Cedric M. Blouin
bioRxiv 281113; doi: https://doi.org/10.1101/281113
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Lack of functional caveolae in Cav3 mutated human dystrophic myotubes results in deficient mechanoprotection and IL6/STAT3 mechanosignaling
Melissa Dewulf, Darius Köster, Bidisha Sinha, Christine Viaris de Lesegno, Valérie Chambon, Anne Bigot, Nicolas Tardif, Ludger Johannes, Pierre Nassoy, Gillian Butler-Browne, Christophe Lamaze, Cedric M. Blouin
bioRxiv 281113; doi: https://doi.org/10.1101/281113

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