Regulation of Duchenne muscular dystrophy through the obestatin/GPR39 system
Although autophagy impairment plays a significant role in the pathogenesis of Duchenne muscular dystrophy (DMD), little is known about the mechanisms by which the autophagic machinery and related signals are influenced by stressors connected to muscular dystrophy. In this work, we describe the unexp...
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| Format: | doctoral thesis |
| Publication Date: | 2025 |
| Country: | España |
| Institution: | Universidad de Santiago de Compostela (USC) |
| Repository: | Minerva. Repositorio Institucional de la Universidad de Santiago de Compostela |
| Language: | English |
| OAI Identifier: | oai:minerva.usc.gal:10347/42101 |
| Online Access: | https://hdl.handle.net/10347/42101 |
| Access Level: | Open access |
| Keyword: | obestatin signaling Duchenne muscular dystrophy autophagy skeletal muscle muscular dystrophy 241104 Fisiología endocrina 241108 Metabolismo humano 241003 Citología humana |
| Summary: | Although autophagy impairment plays a significant role in the pathogenesis of Duchenne muscular dystrophy (DMD), little is known about the mechanisms by which the autophagic machinery and related signals are influenced by stressors connected to muscular dystrophy. In this work, we describe the unexpected finding whereby in the dystrophin-deficient mdx mice and in human immortalized DMD myotubes, the obestatin/GPR39 system activates mTOR concurrently with AMPK to control protein synthesis, ubiquitin-proteasome system, and autophagy-lysosome system. Autophagy-derived amino acids enhance mTOR activity, thereby counteracting muscle wasting in DMD. The pattern of post-translational modifications of the E3 ligase NEDD4-L, including NEDD4-L tyrosine phosphorylation and autoubiquitination, is postulated as the major trigger to activate the autophagy process in response to obestatin. NEDD4-L employs different approaches to coordinate the VPS34 and ULK1 complexes. |
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