S100A9 Mediates Neuroblastoma‐Associated Skeletal Muscle Atrophy via O‐GlcNAcylation Repression and Activate Mitophagy Activation
Jianwei Lin, Yuxin Zhang, Qi Wang, Jingchun Lv, Bingqiang Han, Dapeng JiangABSTRACT
Background
In patients with neuroblastoma (NB), skeletal muscle atrophy is a key factor linked to poor survival and decreased long‐term quality of life. Nevertheless, there are still insufficient therapeutic methods that work, and the underlying mechanisms remain unclear. As persistent inflammation is a hallmark of tumour‐related muscle atrophy, this study aims to identify the key inflammatory mediators causing NB‐related muscle atrophy and systematically elucidate the downstream molecular mechanism.
Methods
The adverse biological features of NB were used to identify potential inflammatory mediators causing muscle atrophy. Serum samples from NB patients and NB mouse models were then used to confirm the clinical relevance of these candidates to skeletal muscle atrophy. Recombinant inflammatory proteins and certain inhibitors were given in vivo to define the functional impact of mediators. Additionally, RNA sequencing (RNA‐seq), quantitative real‐time PCR (qPCR) and Western blotting were used to methodically examine the underlying molecular pathways of NB‐induced muscle atrophy.
Results
Both NB patients with muscle atrophy and NB mouse models had considerably higher serum levels of the pro‐inflammatory mediator S100A9 protein ( p < 0.001). Recombinant mouse S100A9 protein functionally reduced skeletal muscle weight and upregulated the atrophy markers TRIM63/FBXO32 in mice ( p < 0.05), whereas its inhibitor, ABR‐238901, successfully reduced muscle atrophy and downregulated these atrophy markers in the NB model ( p < 0.001). Mechanistically, S100A9 inhibited skeletal muscle protein O‐GlcNAcylation via its receptor RAGE ( p < 0.05). Muscle atrophy was ultimately caused by the abnormal activation of BNIP3/BNIP3L‐mediated mitophagy that resulted from this suppression. Lastly, by inhibiting this mitophagy route, in vivo administration of the O‐GlcNAcylation agonist Thiamet G considerably reduced skeletal muscle atrophy in NB mice ( p < 0.05).
Conclusions
Our study identifies S100A9 as a critical mediator of NB‐associated skeletal muscle atrophy through a novel RAGE/O‐GlcNAcylation/mitophagy axis, establishing S100A9 as a potential therapeutic target and providing a rationale for early interventional strategies to preserve muscle mass and improve patient outcomes.