The protective effect of IL-12/23 neutralizing antibody in sarcopenia associated with dextran sulfate sodium-induced experimental colitis.

Abstract

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 7days. 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 μm2 ± 176.45 of cont. vs. 640.1 μm2 ± 59.83 of DSS + PBS, P < 0.0001; tibialis anterior, 1251.8 μm2 ± 331.48 of cont. vs. 678.9 μm2 ± 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 μm2 ± 59.83 of DSS + PBS vs. 1062.0 μm2 ± 83.41 of DSS + p40Ab, P < 0.0001) and tibialis anterior (678.9 μm2 ± 67.59 of DSS + PBS vs. 1105.3 μm2 ± 143.15 of DSS + p40Ab, P = 0.0003).vs. 640.1μm2 ±59.83 of DSS+PBS, P<0.0001) and tibialis anterior (1251.8μm2 ±331.48 of cont. vs. 678.9μm2 ±67.59 of DSS+PBS, P<0.0001), and the treatment of IL-12/23 p40 neutralizing antibody partially restored CSA of the gastrocnemius (640.1μm2 ±59.83 of DSS+PBS vs. 1062.0μm2 ±83.41 of DSS+p40Ab, P<0.0001) and tibialis anterior (678.9μm2 ±67.59 of DSS+PBS vs. 1105.3μm2 ±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: 139.9g±5.38 of cont. vs. 83.9g±5.48 of DSS+PBS, P<0.0001; DSS+PBS vs. 118.6g±4.05 of DSS+p40Ab, P<0.0001; fatigue distance: 872.5m±104.01 of cont. vs. 58.2m±107.72 of DSS+PBS, P<0.0001; DSS+PBS vs. 328.0m±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.