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Updated: Jan 18, 2026
In Situ Immunofluorescent Staining of Autophagy in Muscle Stem Cells
Published on: June 12, 2017
Obestatin Treatment Counteracts Muscle Wasting by Reactivation of Autophagy in Duchenne Muscular Dystrophy
Icía Santos-Zas1, Silvia Costas-Abalde1,2, Andrea C Lodeiro1,2
1Grupo De Endocrinología Celular Instituto De Investigación Sanitaria De Santiago (IDIS) Complejo Hospitalario Universitario De Santiago (CHUS), Servicio Gallego De Salud (SERGAS), Trav Santiago de Compostela Spain.
Abstract:
The mechanisms by which muscular dystrophy-related stress is transduced to the autophagic machinery remain poorly characterized. The formulation of strategies should be based on how disruption of these processes results in the deregulation of signaling pathways that contribute to many pathological effects of the disease. In this study, we investigated the molecular mechanism by which the obestatin/GPR39 system, an autocrine signaling with anabolic impact on normal skeletal muscle, restores autophagy in Duchenne muscular dystrophy (DMD). We report that obestatin integrates 5' AMP-activated protein kinase (AMPK) and mammalian target of rapamycin complex 1 (mTORC1) signaling to control ubiquitin proteasome system (UPS), autophagy-lysosome system, and protein synthesis under dystrophic context. The posttranslational modifications of the E3 ligase NEDD4-L emerges as the main switch to activate the autophagy in response to obestatin. This includes NEDD4-L tyrosine phosphorylation and autoubiquitination, which is critical for recruiting the ubiquitin-specific protease 10 to assemble a deubiquitination complex, that orchestrates the unc-51 like autophagy activating kinase 1 (ULK1) and class III PI3K (VPS34) complexes. Reactivation of autophagy through obestatin signaling promotes the recovery of physiological skeletal muscle function. Thus, DMD conditions determine permissiveness to the activation of AMPK that sustain autophagy under anabolic conditions stablished by obestatin signaling through mTORC1.
Insights
Obestatin signaling restores autophagy in Duchenne muscular dystrophy (DMD) by activating AMPK and mTORC1 pathways. This process involves NEDD4-L modifications, reactivating the autophagy-lysosome system and improving muscle function.
Area of Science:
- Muscle physiology
- Cellular signaling
- Autophagy research
Background:
- Mechanisms linking muscular dystrophy-related stress to autophagy are unclear.
- Disrupted signaling pathways contribute to Duchenne muscular dystrophy (DMD) pathology.
- The obestatin/GPR39 system has anabolic effects on skeletal muscle.
Purpose of the Study:
- Investigate how the obestatin/GPR39 system restores autophagy in DMD.
- Elucidate the molecular mechanisms involved in obestatin-mediated autophagy.
- Determine the role of signaling pathways in Duchenne muscular dystrophy recovery.
Main Methods:
- Studied the obestatin/GPR39 system in a Duchenne muscular dystrophy context.
- Analyzed the integration of 5' AMP-activated protein kinase (AMPK) and mammalian target of rapamycin complex 1 (mTORC1) signaling.
- Investigated posttranslational modifications of the E3 ligase NEDD4-L and its role in autophagy activation.
Main Results:
- Obestatin integrates AMPK and mTORC1 signaling to regulate ubiquitin proteasome system (UPS), autophagy-lysosome system, and protein synthesis in dystrophic muscle.
- NEDD4-L tyrosine phosphorylation and autoubiquitination activate autophagy by recruiting deubiquitinating enzymes.
- Obestatin signaling reactivates autophagy, promoting recovery of skeletal muscle function in DMD.
Conclusions:
- Obestatin signaling restores autophagy in DMD by modulating AMPK and mTORC1 pathways.
- NEDD4-L acts as a key regulator in obestatin-induced autophagy.
- Reactivation of autophagy via obestatin signaling improves skeletal muscle physiology in Duchenne muscular dystrophy.
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