(Cell Press, 2024) Department of Molecular Biology and Genetics; Department of Molecular Biology and Genetics; Waraich, Aylin Domaniku; Ağca, Samet; Toledo, Batu; Sucuoğlu, Melis; Özen, Sevgi Döndü; Bilgiç, Şevval Nur; Arabacı, Hilal Dilşad; Kashgari, Aynur Erkin; Kır, Serkan; Graduate School of Sciences and Engineering; College of Sciences
Progressive weakness and muscle loss are associated with multiple chronic conditions, including muscular dystrophy and cancer. Cancer-associated cachexia, characterized by dramatic weight loss and fatigue, leads to reduced quality of life and poor survival. Inflammatory cytokines have been implicated in muscle atrophy;however, available anticytokine therapies failed to prevent muscle wasting in cancer patients. Here, we show that oncostatin M (OSM) is a potent inducer of muscle atrophy. OSM triggers cellular atrophy in primary myotubes using the JAK/STAT3 pathway. Identification of OSM targets by RNA sequencing reveals the induction of various muscle atrophy-related genes, including Atrogin1. OSM overexpression in mice causes muscle wasting, whereas muscle-specific deletion of the OSM receptor (OSMR) and the neutralization of circulating OSM preserves muscle mass and function in tumor-bearing mice. Our results indicate that activated OSM/OSMR signaling drives muscle atrophy, and the therapeutic targeting of this pathway may be useful in preventing muscle wasting.
