2. Academic Validation
  3. SH3KBP1 promotes skeletal myofiber formation and functionality through ER/SR architecture integrity

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

  • EMBO Rep. 2025 Mar 10. doi: 10.1038/s44319-025-00413-9.
Alexandre Guiraud # 1,  Nathalie Couturier # 1,  Emilie Christin 1,  Léa Castellano 1,  Marine Daura 1,  Carole Kretz-Remy 1,  Alexandre Janin 1,  Alireza Ghasemizadeh 1,  Peggy Del Carmine 1,  Laloe Monteiro 1,  Ludivine Rotard 1,  Colline Sanchez 1,  Vincent Jacquemond 1,  Claire Burny 2,  Stéphane Janczarski 2,  Anne-Cécile Durieux 3,  David Arnould 3,  Norma Beatriz Romero 4,  Mai Thao Bui 4,  Vladimir L Buchman 5,  Laura Julien 6,  Marc Bitoun 6,  Vincent Gache 7
Affiliations

Affiliations

  • 1 CNRS/UCBL1 UMR 5261 - INSERM U1315, U1217, INMG-PGNM, INSERM, CNRS, Claude Bernard University Lyon 1, Lyon, France.
  • 2 Laboratoire de Biologie et Modélisation de la Cellule, ENS de Lyon, Lyon, CEDEX 07, France.
  • 3 Laboratoire Interuniversitaire de Biologie de la Motricité, Université de Lyon, Université Jean Monnet, Saint Etienne, France.
  • 4 Unité de Morphologie Neuromusculaire, Institut de Myologie, Groupe Hospitalier Universitaire La Pitié-Salpêtrière, Paris, France.
  • 5 School of Biosciences, Cardiff University, Museum Avenue, Cardiff, CF10 3AX, UK.
  • 6 Sorbonne Université, INSERM, Institute of Myology, Centre of Research in Myology, F-75013, Paris, France.
  • 7 CNRS/UCBL1 UMR 5261 - INSERM U1315, U1217, INMG-PGNM, INSERM, CNRS, Claude Bernard University Lyon 1, Lyon, France. Vincent.gache@inserm.fr.
  • # Contributed equally.
PMID: 40065183 DOI: 10.1038/s44319-025-00413-9
Abstract

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.

Keywords

Centronuclear Myopathies; Endoplasmic Reticulum; Myonuclear Positioning; Triads.

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