<br>阻断 IGF2R 可改善肌肉再生并改善杜氏肌营养不良症。,EMBO Molecular Medicine

当前位置： X-MOL 学术 › EMBO Mol. Med. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

阻断 IGF2R 可改善肌肉再生并改善杜氏肌营养不良症。
EMBO Molecular Medicine ( IF 9.0 ) Pub Date : 2019-12-02 , DOI: 10.15252/emmm.201911019
Pamela Bella ₁ , Andrea Farini ₁ , Stefania Banfi ₂ , Daniele Parolini ₃ , Noemi Tonna ₄ , Mirella Meregalli ₁ , Marzia Belicchi ₁ , Silvia Erratico ₅ , Pasqualina D'Ursi ₆ , Fabio Bianco ₄ , Mariella Legato ₁ , Chiara Ruocco ₇ , Clementina Sitzia ₈ , Simone Sangiorgi ₉ , Chiara Villa ₁ , Giuseppe D'Antona ₁₀ , Luciano Milanesi ₆ , Enzo Nisoli ₇ , PierLuigi Mauri ₆ , Yvan Torrente ₁

Affiliation

Stem Cell Laboratory, Department of Pathophysiology and Transplantation, Unit of Neurology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Centro Dino Ferrari, Universitá degli Studi di Milano, Milan, Italy.
Hematology Department Fondazione IRCCS, Department of Oncology and Hemato-oncology, Istituto Nazionale dei Tumori, Universitá degli Studi di Milano, Milan, Italy.
Thermo Fisher Scientific, Life Technologies Italia, Monza, Italy.
Neuro-Zone s.r.l., Open Zone, Milano, Italy.
Novystem Spa, Milan, Italy.
Institute of Technologies in Biomedicine, National Research Council (ITB-CNR), Milan, Italy.
Department of Medical Biotechnology and Translational Medicine, Center for Study and Research on Obesity, Milan University, Milan, Italy.
UOC SMEL-1, Scuola di Specializzazione di Patologia Clinica e Biochimica Clinica, Università degli Studi di Milano, Milan, Italy.
Neurosurgery Unit, Department of Surgery, ASST Lariana-S. Anna Hospital, Como, Italy.
Department of Public Health, Experimental and Forensic Medicine, Pavia University, Pavia, Italy.

杜氏肌营养不良症 (DMD) 是一种使人衰弱的致命性 X 连锁肌肉疾病。最近的研究结果表明，IGF 在骨骼肌再生和发育中发挥着核心作用。在 IGF 中，胰岛素样生长因子 2 (IGF2) 是细胞生长、存活、迁移和分化的关键调节因子。 2 型 IGF 受体 (IGF2R) 通过将 IGF2 靶向溶酶体进行降解来调节 IGF2 的循环和组织水平。我们发现 IGF2R 和钙池操纵的 Ca2+ 通道 CD20 共享一个共同的疏水性结合基序，可以稳定它们的结合。沉默CD20会降低成肌细胞分化，而阻断IGF2R则通过钙调蛋白/钙调神经磷酸酶/NFAT途径增加成肌细胞的增殖和分化。值得注意的是，抗 IGF2R 诱导 CD20 磷酸化，导致肌浆/内质网 Ca2+ -ATP 酶 (SERCA) 激活并去除细胞内 Ca2+。有趣的是，我们发现人类 DMD 患者和 mdx 小鼠营养不良的骨骼肌中 IGF2R 表达增加。通过中和抗体阻断 IGF2R 可刺激营养不良 mdx 小鼠的肌肉再生、诱导力恢复和毛细血管结构正常化，这为开发 DMD 的新生物疗法提供了令人鼓舞的起点。

"点击查看英文标题和摘要"

Blockade of IGF2R improves muscle regeneration and ameliorates Duchenne muscular dystrophy.

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.

更新日期：2020-01-09

点击分享查看原文

点击收藏

公开下载

阅读更多本刊新发论文本刊介绍/投稿指南