Skeletal muscles fibers are formed by the fusion of hundreds of cells where myonuclei are actively spread at myofibers periphery. Growing evidences supports connections between myonuclear positioning and muscle functionality. How myonuclei localization in muscle fibers contributes to muscle efficiency remains poorly characterized. Here, we show that in developing myofibers, SH3KBP1 scaffolds Endoplasmic Reticulum through Calnexin at myonuclei vicinity that in turn controls myonuclei motion and localization. We also demonstrate that SH3KBP1 binds to DNM2 and contribute to Transverse-tubules (T-tubules) formation and maintenance in mature myofibers. Sh3kbp1 mRNA is up regulated in a mouse model of Autosomal Dominant CentroNuclear Myopathy (AD-CNM): Dnm2+/R465W. SH3KBP1 thus appears as a compensation mechanism in this CNM model since its depletion contributes to increase CNM-like phenotypes, impacting parameters such as muscle fibers cross-section areas or slow fibers content. Altogether we identify SH3KBP1 as a new regulator of myonuclear domains establishment in developing muscle fibers through ER scaffolding and contribute to myofibers integrity through T-tubules formation/maintenance.

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