# Obestatin Treatment Counteracts Muscle Wasting by Reactivation of Autophagy in Duchenne Muscular Dystrophy

## TL;DR

Obestatin helps counter muscle wasting in Duchenne muscular dystrophy by reactivating autophagy through specific molecular pathways.

## Contribution

The study reveals a novel mechanism by which obestatin activates autophagy via NEDD4-L in Duchenne muscular dystrophy.

## Key findings

- Obestatin activates autophagy by modifying NEDD4-L through tyrosine phosphorylation and autoubiquitination.
- NEDD4-L recruits USP10 to form a deubiquitination complex that stabilizes VPS34 and promotes autophagy.
- AMPK activation under obestatin signaling sustains autophagy without inhibiting mTORC1 in DMD.

## 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.

Obestatin signaling reactivates autophagy by NEDD4‐L activation under DMD conditions. Tyrosine switch on NEDD4‐L activates autoubiquitination that serves as a scaffold to recruit USP10 to form a deubiquitination complex, which stabilizes VPS34 to promote autophagy by activation of the Beclin1 complex. In parallel, NEDD4‐L favors AMPK exposure to CaMKKß to activate ULK1. Under DMD conditions, AMPK does not inhibit mTORC1, but sustains ULK1/Beclin1 activity and autophagy. Reactivation of autophagy promotes the recovery of physiological skeletal muscle function. In nonpathological conditions, lack of action of non‐RTK on NEDD4‐L favors interaction between c‐Src and NEDD4‐L, thus impairing the VPS34 stabilization and AMPK activation.