Increasing LRP4 diminishes neuromuscular deficits in a mouse model of Duchenne muscular dystrophy
| Autor: | Hongyang Jing, Tiankun Hui, Peng Chen, Shunqi Wang, Daojun Hong, Min Yan, Tian Zhou, Xia Dong, Suqi Zou, Ziyang Liu, Erkang Fei, Dongyan Ren, Xinsheng Lai |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
musculoskeletal diseases AcademicSubjects/SCI01140 congenital hereditary and neonatal diseases and abnormalities China Neuromuscular disease Duchenne muscular dystrophy Muscle Fibers Skeletal Neuromuscular transmission Neuromuscular Junction Mice Transgenic Biology Synaptic Transmission Neuromuscular junction Dystrophin-associated glycoprotein complex Dystrophin 03 medical and health sciences Mice 0302 clinical medicine Glycoprotein complex Genetics medicine Animals Humans Regeneration Muscle Strength Muscle Skeletal Molecular Biology Genetics (clinical) LDL-Receptor Related Proteins Autoantibodies Denervation Agrin General Medicine medicine.disease musculoskeletal system Cell biology Muscular Dystrophy Duchenne Disease Models Animal 030104 developmental biology medicine.anatomical_structure nervous system Mice Inbred mdx General Article 030217 neurology & neurosurgery Muscle Contraction |
| Zdroj: | Human Molecular Genetics |
| ISSN: | 1460-2083 0964-6906 |
| Popis: | Duchenne muscular dystrophy (DMD) is an X-linked neuromuscular disease characterized by progressive wasting of skeletal muscles. The neuromuscular junction (NMJ) is a synapse between motor neurons and skeletal muscle fibers, critical for the control of muscle contraction. The NMJ decline is observed in DMD patients, but the mechanism is unclear. LRP4 serves as a receptor for agrin, a proteoglycan secreted by motor neurons to induce NMJ, and plays a critical role in NMJ formation and maintenance. Interestingly, we found that protein levels of LRP4 were reduced both in muscles of the DMD patients and DMD model mdx mice. We explored whether increasing LRP4 is beneficial for DMD and crossed muscle-specific LRP4 transgenic mice with mdx mice (mdx; HSA-LRP4). The LRP4 transgene increased muscle strength, together with improved neuromuscular transmission in mdx mice. Furthermore, we found the LRP4 expression mitigated NMJ fragments and denervation in mdx mice. Mechanically, we showed that overexpression of LRP4 increased the activity of MuSK and expression of dystrophin-associated glycoprotein complex proteins in the mdx mice. Overall, our findings suggest that increasing LRP4 improves both function and structure of NMJ in the mdx mice and Agrin signaling might serve as a new therapeutic strategy in DMD. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|