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 journalArticle

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
DOIs
Publication statusAccepted/In press - Jan 1 2019

Fingerprint

Duchenne Muscular Dystrophy
Inbred mdx Mouse
Regeneration
Myoblasts
Muscles
Intercellular Signaling Peptides and Proteins
Skeletal Muscle
IGF Type 2 Receptor
Biological Therapy
Calcium-Transporting ATPases
Muscle Development
Calcineurin
Sarcoplasmic Reticulum
Muscular Diseases
Calmodulin
Lysosomes
Neutralizing Antibodies
Endoplasmic Reticulum
Cell Differentiation
Cell Survival

Keywords

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

ASJC Scopus subject areas

  • Molecular Medicine

Cite this

Blockade of IGF2R improves muscle regeneration and ameliorates Duchenne muscular dystrophy. / Bella, Pamela; Farini, Andrea; Banfi, Stefania; Parolini, Daniele; Tonna, Noemi; 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, Pier Luigi; Torrente, Yvan.

In: EMBO Molecular Medicine, 01.01.2019.

Research output: Contribution to journalArticle

Bella, P, Farini, A, Banfi, S, Parolini, D, Tonna, N, Meregalli, M, Belicchi, M, Erratico, S, D'Ursi, P, Bianco, F, Legato, M, Ruocco, C, Sitzia, C, Sangiorgi, S, Villa, C, D'Antona, G, Milanesi, L, Nisoli, E, Mauri, PL & Torrente, Y 2019, 'Blockade of IGF2R improves muscle regeneration and ameliorates Duchenne muscular dystrophy', EMBO Molecular Medicine. https://doi.org/10.15252/emmm.201911019
Bella, Pamela ; Farini, Andrea ; Banfi, Stefania ; Parolini, Daniele ; Tonna, Noemi ; 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, Pier Luigi ; Torrente, Yvan. / Blockade of IGF2R improves muscle regeneration and ameliorates Duchenne muscular dystrophy. In: EMBO Molecular Medicine. 2019.
@article{47a93acc86a84d77bd226e6884db2c49,
title = "Blockade of IGF2R improves muscle regeneration and ameliorates Duchenne muscular dystrophy",
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.",
keywords = "DMD, IGF2, IGF2R, muscle regeneration, muscular dystrophy",
author = "Pamela Bella and Andrea Farini and Stefania Banfi and Daniele Parolini and Noemi Tonna and Mirella Meregalli and Marzia Belicchi and Silvia Erratico and Pasqualina D'Ursi and Fabio Bianco and Mariella Legato and Chiara Ruocco and Clementina Sitzia and Simone Sangiorgi and Chiara Villa and Giuseppe D'Antona and Luciano Milanesi and Enzo Nisoli and Mauri, {Pier Luigi} and Yvan Torrente",
year = "2019",
month = "1",
day = "1",
doi = "10.15252/emmm.201911019",
language = "English",
journal = "EMBO Molecular Medicine",
issn = "1757-4676",
publisher = "Wiley-Blackwell",

}

TY - JOUR

T1 - Blockade of IGF2R improves muscle regeneration and ameliorates Duchenne muscular dystrophy

AU - Bella, Pamela

AU - Farini, Andrea

AU - Banfi, Stefania

AU - Parolini, Daniele

AU - Tonna, Noemi

AU - Meregalli, Mirella

AU - Belicchi, Marzia

AU - Erratico, Silvia

AU - D'Ursi, Pasqualina

AU - Bianco, Fabio

AU - Legato, Mariella

AU - Ruocco, Chiara

AU - Sitzia, Clementina

AU - Sangiorgi, Simone

AU - Villa, Chiara

AU - D'Antona, Giuseppe

AU - Milanesi, Luciano

AU - Nisoli, Enzo

AU - Mauri, Pier Luigi

AU - Torrente, Yvan

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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.

AB - 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.

KW - DMD

KW - IGF2

KW - IGF2R

KW - muscle regeneration

KW - muscular dystrophy

UR - http://www.scopus.com/inward/record.url?scp=85076165041&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85076165041&partnerID=8YFLogxK

U2 - 10.15252/emmm.201911019

DO - 10.15252/emmm.201911019

M3 - Article

C2 - 31793167

AN - SCOPUS:85076165041

JO - EMBO Molecular Medicine

JF - EMBO Molecular Medicine

SN - 1757-4676

M1 - e11019

ER -