Oncostatin M signaling drives cancer-associated skeletal muscle wasting
Aylin Domaniku-Waraich, Samet Agca, Batu Toledo, Melis Sucuoglu, Sevgi Döndü Özen, Şevval Nur Bilgiç, Dilşad H. Arabacı, Aynur Erkin Kashgari, Serkan Kır
Abstract
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.