# Optineurin binding to the novel interacting partner Junction plakoglobin prevents muscle atrophy in mice

## TL;DR

Optineurin prevents muscle atrophy by interacting with Junction plakoglobin and activating the PI3K-AKT pathway in mice.

## Contribution

The study identifies Junction plakoglobin as a novel interacting partner of Optineurin in regulating muscle atrophy.

## Key findings

- Optineurin overexpression alleviates dexamethasone-induced muscle atrophy in mice.
- Optineurin interacts with Junction plakoglobin to activate the PI3K-AKT pathway.
- Pharmacological activation of PI3K-AKT rescues muscle atrophy in Optn-knockdown mice.

## Abstract

Skeletal muscle atrophy is a debilitating condition that significantly affects patients’ quality of life and prognosis, yet its underlying mechanisms remain poorly understood. Here, we identify Optineurin (OPTN) as an active regulator for maintenance of muscle homeostasis during muscle atrophy. Knockdown (KD) of Optn induces muscle atrophy, while overexpression of Optn alleviated dexamethasone-induced muscle atrophy in mice. Mechanistically, we for the first time identified Junction plakoglobin (JUP) as a novel interacting partner of OPTN. OPTN alleviates muscle atrophy in a JUP-dependent manner, corroborating JUP as the downstream effector of OPTN-mediated muscle atrophy. RNA-seq analysis revealed that PI3K-AKT pathway is markedly downregulated in Optn-KD muscle, and pharmacological activation of PI3K-AKT pathway effectively rescued muscle atrophy in Optn-KD mice. We further show that OPTN coordinates the interaction between JUP and PI3-Kinase p85 in muscle, promoting activation of the PI3K-AKT pathway. Collectively, our study proposed a conceptual novelty that OPTN-JUP axis mediated activation of the PI3K-AKT pathway during muscle atrophy. These findings offer new insights into the mechanisms of muscle atrophy and suggest potential therapeutic strategies for this condition.

Skeletal muscle atrophy is a debilitating condition that accompanies a number of diseases, but there are few known therapeutic targets to reverse it. This study identifies Optineurin as a regulator of muscle homeostasis, showing that it binds to JUP and activates the PI3K-AKT pathway to prevent muscle atrophy in mice.