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Myeloma extracellular vesicle-derived RAGE increases inflammatory responses and myotube atrophy in multiple myeloma through activation of the TLR4/NF-κB p65 pathway

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Abstract

Sarcopenia manifests as muscle atrophy and loss that is complicated with malignancy. This study explored the mechanism of extracellular vesicles (EVs) in multiple myeloma (MM) with sarcopenia. SP2/0 conditioned medium (CM) was collected to isolate SP2/0-EVs. C2C12 cells were incubated with SP2/0 CM or SP2/0-EVs. ROS, TNF-α, IL-6, MuRF1 and MyHC levels were detected by DCF-DA fluorescent probe, ELISA, and Western blot. GW4869 was used to inhibit EV secretion in SP2/0 to confirm its effect on muscle atrophy. Serum was collected from MM patients with or without sarcopenia to detect RAGE mRNA expression. SP2/0 cells were transfected with RAGE siRNA and C2C12 cells were treated with the isolated si-RAGE-EVs or/and TLR4 agonist. SP2/0 tumor-bearing mouse model was established. Healthy mice and SP2/0-tumor bearing mice were treated with SP2/0-EVs or si-RAGE-EVs. SP2/0 CM or SP2/0-EVs stimulated ROS, inflammatory responses, and myotube atrophy in C2C12 cells. GW4869 blocked EV secretion and the effects of SP2/0 CM. RAGE mRNA expression in serum EVs was increased in MM&Sarcopenia patients and RAGE knockdown in SP2/0-EVs partially nullified SP2/0-EVs’ effects. SP2/0-EVs activated the TLR4/NF-κB p65 pathway by translocating RAGE. SP2/0-EVs-derived RAGE elevated ROS production, inflammation, and myotube atrophy in C2C12 cells and caused muscle loss in SP2/0 tumor-bearing mice by activating the TLR4/NF-κB p65 pathway. SP2/0-EVs partially recapitulated muscle loss in healthy mice. SP2/0-EVs-derived RAGE increased ROS production, inflammation, and myotube atrophy in MM through TLR4/NF-κB p65 pathway activation.

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Authors and Affiliations

  1. Department of Orthopedics, Beijing Chao-Yang Hospital, Beijing, China

    Yue Wu, Xingchen Yao, Xiangjun Shi, Ziyu Xu, Jie Ren, Ming Shi, Meng Li, Junpeng Liu & Xinru Du

  2. Beijing Chao-Yang Hospital, No.8 Gongti South Rd, Chaoyang District, 100020, Beijing, China

    Xinru Du

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  1. Yue Wu
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YW contributed to the study concepts, study design; YW and XY contributed to the literature research; YW, XY, XS, ZX and JR contributed to the experimental studies and data acquisition; YW, MS, ML, JL and XD contributed to the data analysis and statistical analysis; YW contributed to the manuscript preparation and XD contributed to the manuscript editing and review; All authors read and approved the final manuscript.

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Wu, Y., Yao, X., Shi, X. et al. Myeloma extracellular vesicle-derived RAGE increases inflammatory responses and myotube atrophy in multiple myeloma through activation of the TLR4/NF-κB p65 pathway. Apoptosis 29, 849–864 (2024). https://doi.org/10.1007/s10495-023-01920-7

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