Role of caveolin-3 and caveolae mechanics in muscle pathophysiology

Abstract : Caveolae are plasma membrane invaginations that require caveolin proteins for their biogenesis. Recently, our laboratory reported a new role for caveolae in the cell response to mechanical stress (Sinha et al, Cell, 2011). Mutations in the CAV3 gene (muscle isoform), which lead to Cav3 retention in the Golgi apparatus, are associated with muscular dystrophies (MD). My project consists in identifying the functional link between Cav3 mutations and MDs, which exhibit defects in membrane integrity and repair, and in muscle homeostasis.In Cav3-P28L and Cav3-R26Q mutated human myotubes, I showed a lack of caveolae structures at the plasma membrane. This results in a failed buffering of membrane tension increase upon mechanical stress, which leads to membrane integrity defects. I also showed that the interleukin-6 (IL6) pathway, important for muscle homeostasis, is overactivated in mutant myotubes, showing evidence of a negative regulation of the pathway by Cav3. Furthermore, the IL6 pathway is no longer negatively regulated upon mechanical stress, as it is the case in wild-type (WT) myotubes. Interestingly, mutated myotubes phenocopy Cav3 depletion, and the phenotype is reversible with caveolae reformation upon expression of the WT form of Cav3. This confirms the direct link between Cav3 mutations and the absence of caveolae with failed mechano-protection and IL6/STAT3 mechano-signaling.
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Melissa Dewulf. Role of caveolin-3 and caveolae mechanics in muscle pathophysiology. Cellular Biology. Université Paris-Saclay, 2018. English. ⟨NNT : 2018SACLS067⟩. ⟨tel-02145218⟩

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