Biomedical Research Institute, Gyeongsang National University Hospital, Jinju, Republic of Korea.
Department of Orthopedics, Gyeongsang National University Hospital, Jinju, Republic of Korea.
J Cachexia Sarcopenia Muscle. 2023 Apr;14(2):1096-1106. doi: 10.1002/jcsm.13208. Epub 2023 Mar 5.
The improvement of colitis symptoms by treatment with IL-12/23 p40 neutralizing antibody should increase the muscle mass and the function of the sarcopenia phenotype.
An experimental colitis model was induced by oral administration of 2% dextran sulfate sodium (DSS) for 7 days. During induction of colitis, IL-12/23 p40 neutralizing antibody was injected twice on Days 3 and 5. The total body mass index was measured by dual-energy X-ray absorptiometry. The muscle function was measured by forelimb grip strength and fatigue running distance. The muscle fibre cross-sectional area (CSA) was calculated after the transverse section and haematoxylin and eosin staining, and gene expression was confirmed by RT-qPCR. Differentiated C2C12 cells were used as in vitro models and treated with recombinant IL12/23 proteins to mimic the enhanced cytokines in colitis.
The symptoms of colitis were alleviated by injection of IL-12/23 p40 neutralizing antibody compared with phosphate-buffered saline (PBS), and the disease activity index score was significantly lower on Day 8 (0.0 ± 0.00 of cont. vs. 11.3 ± 0.9 of DSS + PBS, P < 0.0001; DSS + PBS vs. 7.7 ± 1.25 of DSS + p40Ab, P < 0.0001). The CSA of the gastrocnemius and tibialis anterior muscle fibres decreased in mice with DSS-induced colitis (gastrocnemius, 1258.2 μm ± 176.45 of cont. vs. 640.1 μm ± 59.83 of DSS + PBS, P < 0.0001; tibialis anterior, 1251.8 μm ± 331.48 of cont. vs. 678.9 μm ± 67.59 of DSS + PBS, P < 0.0001), and the treatment of IL-12/23 p40 neutralizing antibody partially restored CSA of the gastrocnemius (640.1 μm ± 59.83 of DSS + PBS vs. 1062.0 μm ± 83.41 of DSS + p40Ab, P < 0.0001) and tibialis anterior (678.9 μm ± 67.59 of DSS + PBS vs. 1105.3 μm ± 143.15 of DSS + p40Ab, P = 0.0003).vs. 640.1 μm ± 59.83 of DSS + PBS, P < 0.0001) and tibialis anterior (1251.8 μm ± 331.48 of cont. vs. 678.9 μm ± 67.59 of DSS + PBS, P < 0.0001), and the treatment of IL-12/23 p40 neutralizing antibody partially restored CSA of the gastrocnemius (640.1 μm ± 59.83 of DSS + PBS vs. 1062.0 μm ± 83.41 of DSS + p40Ab, P < 0.0001) and tibialis anterior (678.9 μm ± 67.59 of DSS + PBS vs. 1105.3 μm ± 143.15 of DSS + p40Ab, P = 0.0003). In the evaluation of muscle function, grip strength and fatigue distance decreased by colitis were partially restored (grip strength: 139.9 g ± 5.38 of cont. vs. 83.9 g ± 5.48 of DSS + PBS, P < 0.0001; DSS + PBS vs. 118.6 g ± 4.05 of DSS + p40Ab, P < 0.0001; fatigue distance: 872.5 m ± 104.01 of cont. vs. 58.2 m ± 107.72 of DSS + PBS, P < 0.0001; DSS + PBS vs. 328.0 m ± 109.71 of DSS + p40Ab, P = 0.0015) by injection of IL-12/23 p40 neutralizing antibody.
Our study demonstrates that Il-12/23 acts directly on muscle to induce atrophy, and the IL-12/23 p40 neutralizing antibody is effective not only in suppressing colitis but also in maintaining muscle mass and improving muscle function in an experimental colitis model.
通过使用 IL-12/23 p40 中和抗体治疗，结肠炎症状得到改善，应该会增加肌肉质量和肌减少症表型的功能。
通过口服 2%葡聚糖硫酸钠（DSS）诱导 7 天的实验性结肠炎模型。在结肠炎诱导过程中，在第 3 天和第 5 天注射两次 IL-12/23 p40 中和抗体。通过双能 X 射线吸收法测量总体体重指数。通过前肢握力和疲劳跑步距离测量肌肉功能。通过横切和苏木精和伊红染色后计算肌肉纤维横截面积（CSA），并通过 RT-qPCR 确认基因表达。使用分化的 C2C12 细胞作为体外模型，并使用重组 IL12/23 蛋白处理以模拟结肠炎中增强的细胞因子。
与磷酸盐缓冲液（PBS）相比，注射 IL-12/23 p40 中和抗体可减轻结肠炎的症状，第 8 天疾病活动指数评分明显降低（0.0 ± 0.00 与 cont. 相比，DSS + PBS 为 11.3 ± 0.9，P < 0.0001；DSS + PBS 与 DSS + p40Ab 相比，P < 0.0001）。DSS 诱导的结肠炎小鼠的比目鱼肌和胫骨前肌纤维 CSA 减小（比目鱼肌，1258.2 ± 176.45 μm 与 cont. 相比，DSS + PBS 为 640.1 ± 59.83 μm，P < 0.0001；胫骨前肌，1251.8 ± 331.48 μm 与 cont. 相比，DSS + PBS 为 678.9 ± 67.59 μm，P < 0.0001），而 IL-12/23 p40 中和抗体的治疗部分恢复了比目鱼肌的 CSA（DSS + PBS 为 640.1 ± 59.83 μm 与 cont. 相比，DSS + p40Ab 为 1062.0 ± 83.41 μm，P < 0.0001）和胫骨前肌（DSS + PBS 为 678.9 ± 67.59 μm 与 cont. 相比，DSS + p40Ab 为 1105.3 ± 143.15 μm，P = 0.0003）。与 cont. 相比，DSS + PBS 为 640.1 ± 59.83 μm，P < 0.0001）和胫骨前肌（1251.8 ± 331.48 μm 与 cont. 相比，DSS + PBS 为 678.9 ± 67.59 μm，P < 0.0001），而 IL-12/23 p40 中和抗体的治疗部分恢复了比目鱼肌的 CSA（DSS + PBS 为 640.1 ± 59.83 μm 与 cont. 相比，DSS + p40Ab 为 1062.0 ± 83.41 μm，P < 0.0001）和胫骨前肌（DSS + PBS 为 678.9 ± 67.59 μm 与 cont. 相比，DSS + p40Ab 为 1105.3 ± 143.15 μm，P = 0.0003）。在肌肉功能评估中，握力和疲劳距离的下降部分通过结肠炎得到恢复（握力：139.9 ± 5.38 g 与 cont. 相比，DSS + PBS 为 83.9 ± 5.48 g，P < 0.0001；DSS + PBS 与 DSS + p40Ab 相比，P < 0.0001）；疲劳距离：872.5 m 与 cont. 相比，DSS + PBS 为 58.2 m ± 107.72 m，P < 0.0001；DSS + PBS 与 DSS + p40Ab 相比，P = 0.0015）通过注射 IL-12/23 p40 中和抗体。
我们的研究表明，IL-12/23 直接作用于肌肉引起萎缩，IL-12/23 p40 中和抗体不仅在抑制结肠炎方面有效，而且在实验性结肠炎模型中维持肌肉质量和改善肌肉功能方面也有效。
