EDA2R/NIK signaling promotes skeletal muscle atrophy linked to cancer cachexia

Abstract

Skeletal muscle atrophy is a hallmark of the cachexia syndrome that is associated with poor survival and reduced quality of life in cancer patients1. Muscle atrophy involves excessive protein catabolism and loss of muscle mass and strength2. An effective therapy against muscle wasting is lacking as mechanisms driving the atrophy process remain incompletely understood. Our gene expression analysis in muscle tissues revealed upregulation of Ectodysplasin A2 Receptor (EDA2R) in tumor-bearing mice and cachectic cancer patients. Here we show that activation of EDA2R signaling promotes skeletal muscle atrophy. Stimulation of primary myotubes with EDA2R ligand, EDA-A2, triggered pronounced cellular atrophy via inducing the expression of muscle atrophy-related genes Atrogin1 and MuRF1. EDA-A2-driven myotube atrophy involved activation of the noncanonical NF{kappa}B pathway and depended on NIK kinase activity. While EDA-A2 overexpression induced muscle wasting in mice, the deletion of EDA2R or muscle NIK protected tumor-bearing mice from the loss of muscle mass and function. Tumor-induced Oncostatin M upregulated muscle EDA2R expression and muscle-specific Oncostatin M Receptor (OSMR) knockout mice were resistant to tumor-driven muscle wasting. Our results demonstrate that EDA2R/NIK signaling mediates cancer-associated muscle atrophy in an OSM/OSMR-dependent manner. Thus, therapeutic targeting of these pathways may be beneficial in preventing muscle loss.