Skeletal muscle atrophy is a hallmark of the cachexia syndrome that is associated with poor survival and reduced quality of life in cancer patients 1 . Muscle atrophy involves excessive protein catabolism and loss of muscle mass and strength 2 . 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 NFĸB 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.Skeletal muscle atrophy is characterized by excessive protein catabolism leading to loss of muscle mass and strength 2 . Muscle loss is associated with aging (i.e., sarcopenia), muscular dystrophies and the cachexia syndrome that is linked to chronic diseases such as cancer and kidney failure.Cachexia involves progressive muscle wasting that is often accompanied by the loss of adipose tissue 3 . Cachexia is highly prevalent in patients with lung, gastric, pancreatic or colorectal cancers

Skeletal muscle atrophy is a hallmark of the cachexia syndrome that is associated with poor survival and reduced quality of life in cancer patients. Muscle atrophy involves excessive protein catabolism and loss of muscle mass and strength. 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 NFĸB 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.

Background Lung cancer is the primary cause of cancer deaths worldwide. Activation of epidermal growth factor receptor (EGFR) leads to lung cancer progression and poor prognosis while involuntary weight loss remains a major problem. Tumour-derived parathyroid hormone-related protein (PTHrP) emerged as a potential mediator of cachexia. Here, we investigated the modulatory role of EGFR signalling in PTHrP (encoded by Pthlh) gene expression and the impact of this relationship on cancer cachexia. Methods Global gene expression profiles of Lewis lung carcinoma (LLC) cells were analysed. Pthlh mRNA levels were measured by qRT-PCR in LLC cells treated with EGFR ligands and tyrosine kinase inhibitors (TKIs). LLC tumour-bearing mice received EGFR TKI erlotinib for 7 days via intraperitoneal injection or oral gavage. Tumour Pthlh mRNA, weight of fat/muscle tissue, and grip strength were assessed. RNA-seq data from The Cancer Genome Atlas and gene expression analysis tools were used to characterize expression profiles of PTHLH and EGFR along with correlation analysis of PTHLH with EGFR and transforming growth factor alpha (TGFA) in human lung cancer and head and neck squamous carcinoma (HNSC). Survival of lung squamous cell carcinoma (LUSC) and lung adenocarcinoma (LUAD) patients with EGFR gene alterations was analysed in regard to PTHLH expression. Results Expression of EGFR ligands, EGFR itself, and PTHrP co-clusters in LLC cells. Activation of EGFR signalling with its ligands significantly increases (3.8-fold, P < 0.0005) while EGFR TKIs significantly decrease (90%, P < 0.0005) Pthlh mRNA levels in LLC cells. Pthlh mRNA drops 65-75% (P < 0.0005) in tumours upon treatment of LLC tumour-bearing mice with erlotinib while their muscle mass and grip strength increase (9.2% P < 0.05, 23% P < 0.005, respectively) compared with tumour-bearing control mice. PTHLH is overexpressed in tumours of LUSC (45.8-fold, P < 0.05) and HNSC (17.5-fold, P < 0.05) compared with normal tissue. PTHLH expression correlates with EGFR and its ligand TGFA in both cancers (LUSC: n = 745, R = 0.32, P < 0.0001 and R = 0.51, P < 0.0001; HNSC: n = 545, R = 0.34, P < 0.001 and R = 0.50, P < 0.001, respectively). High PTHLH mRNA associates with poor overall survival in LUAD patients with activating EGFR mutations (n = 40, log-rank test, P = 0.0451). Conclusions Epidermal growth factor receptor signalling regulates expression of cachexia mediator PTHrP. EGFR inhibition reduces PTHrP expression in LLC tumours and ameliorates cachexia in LLC tumour-bearing mice.

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 anti-cytokine therapies failed to prevent muscle wasting in cancer patients. We previously reported that muscle-specific deletion of the Oncostatin M (OSM) receptor (OSMR) preserved muscle mass and function in tumor-bearing mice. Here, we show that OSM is a potent inducer of muscle atrophy. OSM triggers cellular atrophy in primary myotubes utilizing the JAK/STAT3 pathway. Identification of OSM targets by RNA sequencing revealed the induction of various muscle atrophy-related genes, including Atrogin1. OSM overexpression in mice caused muscle wasting while the neutralization of circulating OSM protected from tumor-driven loss of muscle mass and function. 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.