Regulation of myonuclear positioning and muscle function by the skeletal muscle-specific CIP protein

Proc Natl Acad Sci U S A. 2020 Aug 11;117(32):19254-19265. doi: 10.1073/pnas.1922911117. Epub 2020 Jul 27.

Abstract

The appropriate arrangement of myonuclei within skeletal muscle myofibers is of critical importance for normal muscle function, and improper myonuclear localization has been linked to a variety of skeletal muscle diseases, such as centronuclear myopathy and muscular dystrophies. However, the molecules that govern myonuclear positioning remain elusive. Here, we report that skeletal muscle-specific CIP (sk-CIP) is a regulator of nuclear positioning. Genetic deletion of sk-CIP in mice results in misalignment of myonuclei along the myofibers and at specialized structures such as neuromuscular junctions (NMJs) and myotendinous junctions (MTJs) in vivo, impairing myonuclear positioning after muscle regeneration, leading to severe muscle dystrophy in mdx mice, a mouse model of Duchenne muscular dystrophy. sk-CIP is localized to the centrosome in myoblasts and relocates to the outer nuclear envelope in myotubes upon differentiation. Mechanistically, we found that sk-CIP interacts with the Linker of Nucleoskeleton and Cytoskeleton (LINC) complex and the centriole Microtubule Organizing Center (MTOC) proteins to coordinately modulate myonuclear positioning and alignment. These findings indicate that sk-CIP may function as a muscle-specific anchoring protein to regulate nuclear position in multinucleated muscle cells.

Keywords: LINC complex; MTOC; nuclear positioning; sk-CIP protein; skeletal muscle.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Cell Nucleus / genetics
  • Cell Nucleus / metabolism*
  • Co-Repressor Proteins
  • Humans
  • Mice
  • Mice, Inbred mdx
  • Mice, Knockout
  • Muscle, Skeletal / metabolism*
  • Muscle, Skeletal / physiopathology
  • Myoblasts / metabolism*
  • Myopathies, Structural, Congenital / genetics
  • Myopathies, Structural, Congenital / metabolism
  • Myopathies, Structural, Congenital / physiopathology*
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Organ Specificity

Substances

  • Carrier Proteins
  • Co-Repressor Proteins
  • MLIP protein, mouse
  • Nuclear Proteins