Blockade of IGF2R improves muscle regeneration and ameliorates Duchenne muscular dystrophy

Pamela Bella, Andrea Farini, Stefania Banfi, Daniele Parolini, Noemi Tonna, Mirella Meregalli, Marzia Belicchi, Silvia Erratico, Pasqualina D'Ursi, Fabio Bianco, Mariella Legato, Chiara Ruocco, Clementina Sitzia, Simone Sangiorgi, Chiara Villa, Giuseppe D'Antona, Luciano Milanesi, Enzo Nisoli, Pier Luigi Mauri, Yvan Torrente

Research output: Contribution to journalArticlepeer-review

Abstract

Duchenne muscular dystrophy (DMD) is a debilitating fatal X-linked muscle disorder. Recent findings indicate that IGFs play a central role in skeletal muscle regeneration and development. Among IGFs, insulinlike growth factor 2 (IGF2) is a key regulator of cell growth, survival, migration and differentiation. The type 2 IGF receptor (IGF2R) modulates circulating and tissue levels of IGF2 by targeting it to lysosomes for degradation. We found that IGF2R and the store-operated Ca2+ channel CD20 share a common hydrophobic binding motif that stabilizes their association. Silencing CD20 decreased myoblast differentiation, whereas blockade of IGF2R increased proliferation and differentiation in myoblasts via the calmodulin/calcineurin/NFAT pathway. Remarkably, anti-IGF2R induced CD20 phosphorylation, leading to the activation of sarcoplasmic/endoplasmic reticulum Ca2+-ATPase (SERCA) and removal of intracellular Ca2+. Interestingly, we found that IGF2R expression was increased in dystrophic skeletal muscle of human DMD patients and mdx mice. Blockade of IGF2R by neutralizing antibodies stimulated muscle regeneration, induced force recovery and normalized capillary architecture in dystrophic mdx mice representing an encouraging starting point for the development of new biological therapies for DMD.

Original languageEnglish
Article numbere11019
JournalEMBO Molecular Medicine
Volume12
Issue number1
DOIs
Publication statusPublished - 2020

Keywords

  • DMD
  • IGF2
  • IGF2R
  • muscle regeneration
  • muscular dystrophy

ASJC Scopus subject areas

  • Molecular Medicine

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