Open AccessBlockade of IGF2R improves muscle regeneration and ameliorates Duchenne muscular dystrophy
Author(s) -
Bella Pamela,
Farini Andrea,
Banfi Stefania,
Parolini Daniele,
Tonoemi,
Meregalli Mirella,
Belicchi Marzia,
Erratico Silvia,
D'Ursi Pasqualina,
Bianco Fabio,
Legato Mariella,
Ruocco Chiara,
Sitzia Clementina,
Sangiorgi Simone,
Villa Chiara,
D'Antona Giuseppe,
Milanesi Luciano,
Nisoli Enzo,
Mauri PierLuigi,
Torrente Yvan
Publication year - 2019
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.201911019
Subject(s) - transplantation , medicine , humanities , art
Duchenne muscular dystrophy ( DMD ) is a debilitating fatal X‐linked muscle disorder. Recent findings indicate that IGF s play a central role in skeletal muscle regeneration and development. Among IGF s, insulinlike growth factor 2 ( IGF 2) is a key regulator of cell growth, survival, migration and differentiation. The type 2 IGF receptor ( IGF 2R) modulates circulating and tissue levels of IGF 2 by targeting it to lysosomes for degradation. We found that IGF 2R and the store‐operated Ca 2+ channel CD 20 share a common hydrophobic binding motif that stabilizes their association. Silencing CD 20 decreased myoblast differentiation, whereas blockade of IGF 2R increased proliferation and differentiation in myoblasts via the calmodulin/calcineurin/ NFAT pathway. Remarkably, anti‐ IGF 2R induced CD 20 phosphorylation, leading to the activation of sarcoplasmic/endoplasmic reticulum Ca 2+ ‐ ATP ase ( SERCA ) and removal of intracellular Ca 2+ . Interestingly, we found that IGF 2R expression was increased in dystrophic skeletal muscle of human DMD patients and mdx mice. Blockade of IGF 2R 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 .