目的 探究消退素D2对糖尿病性肌少症大鼠肌肉萎缩的改善及作用机制。方法 将40只雄性SD大鼠随机分为对照组、模型组、二甲双胍组、消退素D2组、消退素D2＋G蛋白偶联受体18（GPR18）拮抗剂（O-1918）组。采用高糖高脂饮食联合注射链脲佐菌素构建糖尿病性肌少症大鼠模型。检测大鼠骨骼肌指数、肌肉功能，评估大鼠胰岛素抵抗程度，苏木精-伊红（HE）染色检测肌纤维形态，ELISA实验检测血清白细胞介素（IL）-6、肿瘤坏死因子-α（TNF-α）、IL-1β水平，RT-qPCR实验检测诱导型一氧化氮合酶（iNOS）、精氨酸酶1（Arg-1）mRNA表达水平，Western blotting实验检测GPR18、磷酸化-核因子-κB p65（p-NF-κB p65）/NF-κB p65、肌萎缩蛋白Fbox-1（Atrogin-1）、肌肉特异性环指蛋白1（MuRF-1）蛋白表达量。结果 与模型组比较，消退素D2组大鼠腓肠肌形态恢复，体质量、空腹血糖（FPG）、空腹胰岛素（FINS）和胰岛素抵抗指数（IRI），血清促炎因子（IL-6、TNF-α、IL-1β）水平，腓肠肌组织iNOS mRNA表达水平，Atrogin-1、MuRF-1和p-NF-κB 65/NF-κB 65蛋白表达量明显下降；骨骼肌质量和骨骼肌指数、前肢绝对抓力、Arg-1 mRNA表达水平、GPR18蛋白表达量明显升高（P＜0.05）。与消退素D2组相比，消退素D2＋O-1918组大鼠骨骼肌萎缩程度加重，体质量、FPG、FINS和IRI，血清促炎因子水平，腓肠肌组织iNOS mRNA表达水平，Atrogin-1、MuRF-1和p-NF-κB 65/NF-κB 65蛋白表达量显著升高；骨骼肌质量和骨骼肌指数、前肢绝对抓力、Arg-1 mRNA表达水平、GPR18蛋白表达量降低（P＜0.05）。结论 消退素D2可有效改善糖尿病性肌少症大鼠的骨骼肌萎缩状态、增强肌肉功能，其作用机制可能与消退素D2结合GPR18受体进而抑制NF-κB信号通路激活有关。

Objective To explore the improvement effect and mechanism of resolvin D2 on muscle atrophy in rats with diabetic sarcopenia. Methods Forty male SD rats were randomly separated into the control group, model group, metformin group, resolvin D2 group, and resolvin D2 + GPR18 antagonist (O-1918) group. Diabetic sarcopenia rat model was established by a high-glucose and high-fat diet combined with streptozotocin injection. The skeletal muscle index and muscle function of rats were measured, and the degree of insulin resistance in rats was evaluated. The morphology of muscle fibers was detected by HE staining. Levels of serum inflammatory factors (IL-6, TNF-α, and IL-1β) were detected by ELISA experiment. The expression levels of iNOS and Arg-1 mRNAs were measured by RT-qPCR experiment, and the expression levels of GPR18, p-NF-κB p65/NF-κB p65, Atrogin-1 and MuRF-1 proteins were measured by Western blotting experiment. Results Compared with the model group, the gastrocnemius muscle morphology of rats in the resolvin D2 group were recovered. The body weight, FPG, FINS, IRI, the levels of serum pro-inflammatory factors (IL-6, TNF-α, and IL-1β), the expression level of iNOS mRNA in gastrocnemius muscle tissue, and the expression levels of Atrogin-1, MuRF-1 and p-NF-κB 65/NF-κB 65 proteins were obviously decreased, while the skeletal muscle mass, skeletal muscle index, absolute grip strength of the forelimbs, the expression level of Arg-1 mRNA, and the expression level of GPR18 protein were obviously increased (P < 0.05). Compared with the resolvin D2 group, the degree of skeletal muscle atrophy of rats in the resolvin D2 + O-1918 group was aggravated. The body weight, FPG, FINS, IRI, levels of serum pro-inflammatory factors, the expression level of iNOS mRNA in gastrocnemius muscle tissue, and the expression levels of Atrogin-1, MuRF-1 and p-NF-κB 65/NF-κB 65 proteins were obviously increased, while the skeletal muscle mass, skeletal muscle index, absolute grip strength of the forelimbs, the expression level of Arg-1 mRNA, and the expression level of GPR18 protein were obviously decreased (P < 0.05). Conclusion Resolvin D2 can effectively improve the skeletal muscle atrophy state and enhance muscle function in diabetic sarcopenia rats. Its mechanism of action may be related to the binding of resolvin D2 to the GPR18 receptor and its subsequent inhibition of the activation of the NF-κB signaling pathway.

R977

新疆维吾尔自治区自然科学基金资助项目（2023D01C209）