EDA2R–NIK signalling promotes muscle atrophy linked to cancer cachexia

• Published in: Nature (London) 2023-05, Vol.617 (7962), p.827-834
• Main Authors: Bilgic, Sevval Nur, Domaniku, Aylin, Toledo, Batu, Agca, Samet, Weber, Bahar Z. C., Arabaci, Dilsad H., Ozornek, Zeynep, Lause, Pascale, Thissen, Jean-Paul, Loumaye, Audrey, Kir, Serkan
• Format: Article
• Language: English
• Subjects: 13/106; 13/95; 14/63; 38/77; 42/70; 631/67; 631/80/86; 64/60; 82/29; 82/51; 82/80; Animals; Atrophy; Biopsy; Cachexia; Cachexia - complications; Cachexia - etiology; Cachexia - metabolism; Cachexia - pathology; Cancer; Catabolism; Ectodysplasin; Gene expression; Humanities and Social Sciences; Humans; Kinases; Ligands; Mice; multidisciplinary; Muscle Fibers, Skeletal - metabolism; Muscles; Muscular Atrophy - etiology; Muscular Atrophy - metabolism; Muscular Atrophy - pathology; Muscular Atrophy - prevention & control; Muscular dystrophy; Musculoskeletal system; Myotubes; Neoplasms - complications; Neoplasms - metabolism; Neoplasms - pathology; NF-kappaB-Inducing Kinase; NF-κB protein; Oncostatin M; Oncostatin M - metabolism; Pancreatic cancer; Phosphorylation; Proteins; Quality of life; Receptors; Receptors, Oncostatin M - metabolism; Science; Science (multidisciplinary); Signal Transduction; Signaling; Skeletal muscle; Therapeutic targets; Tumor necrosis factor-TNF; Tumors; Xedar Receptor - metabolism
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-023-06047-y

Skeletal muscle atrophy is a hallmark of the cachexia syndrome that is associated with poor survival and reduced quality of life in patients with cancer 1 . Muscle atrophy involves excessive protein catabolism and loss of muscle mass and strength 2 . An effective therapy against muscle wasting is currently lacking because mechanisms driving the atrophy process remain incompletely understood. Our gene expression analysis in muscle tissues indicated upregulation of ectodysplasin A2 receptor (EDA2R) in tumour-bearing mice and patients with cachectic cancer. Here we show that activation of EDA2R signalling promotes skeletal muscle atrophy. Stimulation of primary myotubes with the EDA2R ligand EDA-A2 triggered pronounced cellular atrophy by induction of the expression of muscle atrophy-related genes Atrogin1 and MuRF1 . EDA-A2-driven myotube atrophy involved activation of the non-canonical NFĸB pathway and was dependent on NFκB-inducing kinase (NIK) activity. Whereas EDA-A2 overexpression promoted muscle wasting in mice, deletion of either EDA2R or muscle NIK protected tumour-bearing mice from loss of muscle mass and function. Tumour-induced oncostatin M (OSM) upregulated muscle EDA2R expression, and muscle-specific oncostatin M receptor (OSMR)-knockout mice were resistant to tumour-induced muscle wasting. Our results demonstrate that EDA2R–NIK signalling mediates cancer-associated muscle atrophy in an OSM–OSMR-dependent manner. Thus, therapeutic targeting of these pathways may be beneficial in prevention of muscle loss. Gene expression analysis in muscle tissues showed upregulation of ectodysplasin A2 receptor in tumour-bearing mice and patients with cachectic cancer, and thus therapeutic targeting of relevant pathways may be beneficial in prevention of muscle loss.