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EDA2R–NIK signalling promotes muscle atrophy linked to cancer cachexia

Author

Listed:
  • Sevval Nur Bilgic

    (Koc University)

  • Aylin Domaniku

    (Koc University)

  • Batu Toledo

    (Koc University)

  • Samet Agca

    (Koc University)

  • Bahar Z. C. Weber

    (Koc University)

  • Dilsad H. Arabaci

    (Koc University)

  • Zeynep Ozornek

    (Koc University)

  • Pascale Lause

    (Université Catholique de Louvain)

  • Jean-Paul Thissen

    (Université Catholique de Louvain
    Cliniques Universitaires Saint-Luc)

  • Audrey Loumaye

    (Université Catholique de Louvain
    Cliniques Universitaires Saint-Luc)

  • Serkan Kir

    (Koc University)

Abstract

Skeletal muscle atrophy is a hallmark of the cachexia syndrome that is associated with poor survival and reduced quality of life in patients with cancer1. Muscle atrophy involves excessive protein catabolism and loss of muscle mass and strength2. 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.

Suggested Citation

  • Sevval Nur Bilgic & Aylin Domaniku & Batu Toledo & Samet Agca & Bahar Z. C. Weber & Dilsad H. Arabaci & Zeynep Ozornek & Pascale Lause & Jean-Paul Thissen & Audrey Loumaye & Serkan Kir, 2023. "EDA2R–NIK signalling promotes muscle atrophy linked to cancer cachexia," Nature, Nature, vol. 617(7962), pages 827-834, May.
  • Handle: RePEc:nat:nature:v:617:y:2023:i:7962:d:10.1038_s41586-023-06047-y
    DOI: 10.1038/s41586-023-06047-y
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