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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\u2010activated protein kinase (AMPK) and mammalian target of rapamycin complex 1 (mTORC1) signaling to control ubiquitin proteasome system (UPS), autophagy\u2013lysosome system, and protein synthesis under dystrophic context. The posttranslational modifications of the E3 ligase NEDD4\u2010L emerges as the main switch to activate the autophagy in response to obestatin. This includes NEDD4\u2010L tyrosine phosphorylation and autoubiquitination, which is critical for recruiting the ubiquitin\u2010specific protease 10 to assemble a deubiquitination complex, that orchestrates the unc\u201051 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.<\/jats:p>","DOI":"10.1002\/mco2.70563","type":"journal-article","created":{"date-parts":[[2026,1,14]],"date-time":"2026-01-14T20:29:00Z","timestamp":1768422540000},"source":"Crossref","is-referenced-by-count":0,"title":["Obestatin Treatment Counteracts Muscle Wasting by Reactivation of Autophagy in Duchenne Muscular Dystrophy"],"prefix":"10.1002","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0310-9074","authenticated-orcid":false,"given":"Ic\u00eda","family":"Santos\u2010Zas","sequence":"first","affiliation":[{"name":"Grupo De Endocrinolog\u00eda Celular Instituto De Investigaci\u00f3n Sanitaria De Santiago (IDIS) Complejo Hospitalario Universitario De Santiago (CHUS), Servicio Gallego De Salud (SERGAS), Trav  Santiago de Compostela 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