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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. Epub 2020 Jul 27
Jianming Liu 1 , Zhan-Peng Huang 2 , Mao Nie 3 , Gang Wang 1 , William J Silva 4 , Qiumei Yang 5 , Paula P Freire 6 , Xiaoyun Hu 1 , Huaqun Chen 7 , Zhongliang Deng 3 , William T Pu 8 , Da-Zhi Wang 8
Jianming Liu 1 , Zhan-Peng Huang 2 , Mao Nie 3 , Gang Wang 1 , William J Silva 4 , Qiumei Yang 5 , Paula P Freire 6 , Xiaoyun Hu 1 , Huaqun Chen 7 , Zhongliang Deng 3 , William T Pu 8 , Da-Zhi Wang 8
+ et al

[No authors listed]

Author information
  • 1 Department of Cardiology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115.
  • 2 Center for Translational Medicine, National Health Commission (NHC) Key Laboratory of Assisted Circulation, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510275, China.
  • 3 Department of Orthopaedic Surgery, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, 400010, China.
  • 4 Laboratório de Biologia Celular e Molecular do Músculo Estriado, University of São Paulo, CEP 05508-000 Cidade Universitária, São Paulo, Brazil.
  • 5 Department of Animal Sciences, Sichuan Agriculture University, Chengdu, 611130, China.
  • 6 Department of Morphology, Institute of Biosciences, São Paulo State University, CEP 18618-000, Botucatu, São Paulo, Brazil.
  • 7 Department of Biology, Nanjing Normal University, Nanjing, 225300, China.
  • 8 Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138.

摘要


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 (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