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

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.