Caveolae rings form platforms for Amphiphysin2/Bin1-mediated T-tubule initiation

Caveolae have been proposed to participate in the formation of the T-tubule system in skeletal muscle but to date, mechanistic understanding of the tubulation process per se is cruelly lacking. Here, we developed a two-colour super-resolution and platinum replica correlative electron microscopy technique to visualise caveolae during critical steps of T-tubule formation in extensively differentiated mouse and human genetically modified myotubes. We discovered novel structures formed by caveolin-3, that we termed caveolae rings, which assemble into circular structures. We show that the initial T-tubule membrane forms by fusion of caveolae mediated by Bin1 and that nascent t-tubules enriched in the DHPR calcium channel emanate from caveolae rings. Lastly, we show that caveolae ring formation is defective in human myotubes from caveolinopathy patients with caveolin-3 mutations leading to defective t-tubule formation in adult muscle.

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Vassilopoulos S, Gibaud S, Jimenez A, Caillol G, Leterrier C. Ultrastructure of the axonal periodic scaffold reveals a braid-like organization of actin rings. Nat Commun. 2019 Dec 20;10(1):5803. doi: 10.1038/s41467-019-13835-6.

Parton RG, Del Pozo MA, Vassilopoulos S, Nabi IR, Le Lay S, Lundmark R, Kenworthy AK, Camus A, Blouin CM, Sessa WC, Lamaze C. Caveolae: The FAQs. Traffic. 2020 Jan;21(1):181-185. doi: 10.1111/tra.12689.

Torrino S, Shen WW, Blouin CM, Mani SK, Viaris de Lesegno C, Bost P, Grassart A, Köster D, Valades-Cruz CA, Chambon V, Johannes L, Pierobon P, Soumelis V, Coirault C, Vassilopoulos S, Lamaze C. EHD2 is a mechanotransducer connecting caveolae dynamics with gene transcription. J Cell Biol. 2018 Dec 3;217(12):4092-4105. doi: 10.1083/jcb.201801122.