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<p>Dynamic changes in the arrangement of myonuclei and the organization of the sarcoplasmic reticulum are important determinants of myofiber formation and muscle function. To find factors associated with muscle integrity, we perform an siRNA screen and identify SH3KBP1 as a new factor controlling myoblast fusion, myonuclear positioning, and myotube elongation. We find that the N-terminus of SH3KBP1 binds to dynamin-2 while the C-terminus associates with the endoplasmic reticulum through calnexin, which in turn control myonuclei dynamics and ER integrity, respectively. Additionally, in mature muscle fibers, SH3KBP1 contributes to the formation of triads and modulates the Excitation-Contraction Coupling process efficiency. In Dnm2<sup>R465W/+</sup> mice, a model for centronuclear myopathy (CNM), depletion of Sh3kbp1 expression aggravates CNM-related atrophic phenotypes and impaired autophagic flux in mutant skeletal muscle fiber. Altogether, our results identify SH3KBP1 as a new regulator of myofiber integrity and function.</p>

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SH3KBP1 promotes skeletal myofiber formation and functionality through ER/SR architecture integrity

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年3月10日

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  • Alexandre Guiraud,
  • Nathalie Couturier,
  • Emilie Christin,
  • Léa Castellano,
  • Marine Daura,
  • Carole Kretz-Remy,
  • Alexandre Janin,
  • Alireza Ghasemizadeh,
  • Peggy del Carmine,
  • Laloe Monteiro,
  • Ludivine Rotard,
  • Colline Sanchez,
  • Vincent Jacquemond,
  • Claire Burny,
  • Stéphane Janczarski,
  • Anne-Cécile Durieux,
  • David Arnould,
  • Norma Beatriz Romero,
  • Mai Thao Bui,
  • Vladimir L Buchman,
  • Laura Julien,
  • Marc Bitoun,
  • Vincent Gache

摘要

Dynamic changes in the arrangement of myonuclei and the organization of the sarcoplasmic reticulum are important determinants of myofiber formation and muscle function. To find factors associated with muscle integrity, we perform an siRNA screen and identify SH3KBP1 as a new factor controlling myoblast fusion, myonuclear positioning, and myotube elongation. We find that the N-terminus of SH3KBP1 binds to dynamin-2 while the C-terminus associates with the endoplasmic reticulum through calnexin, which in turn control myonuclei dynamics and ER integrity, respectively. Additionally, in mature muscle fibers, SH3KBP1 contributes to the formation of triads and modulates the Excitation-Contraction Coupling process efficiency. In Dnm2R465W/+ mice, a model for centronuclear myopathy (CNM), depletion of Sh3kbp1 expression aggravates CNM-related atrophic phenotypes and impaired autophagic flux in mutant skeletal muscle fiber. Altogether, our results identify SH3KBP1 as a new regulator of myofiber integrity and function.