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

EMBO Rep. 2025 Apr;26(8):2166-2191. doi: 10.1038/s44319-025-00413-9. Epub 2025 Mar 10.

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.

MeSH terms

  • Adaptor Proteins, Signal Transducing* / genetics
  • Adaptor Proteins, Signal Transducing* / metabolism
  • Animals
  • Dynamin II / genetics
  • Dynamin II / metabolism
  • Endoplasmic Reticulum* / metabolism
  • Humans
  • Mice
  • Muscle Fibers, Skeletal* / metabolism
  • Muscle, Skeletal / metabolism
  • Myoblasts / metabolism
  • Myopathies, Structural, Congenital / genetics
  • Myopathies, Structural, Congenital / metabolism
  • Myopathies, Structural, Congenital / pathology
  • Protein Binding
  • Sarcoplasmic Reticulum* / metabolism

Substances

  • Dynamin II
  • Adaptor Proteins, Signal Transducing
  • DNM2 protein, mouse