Bone and Joint Research Unit, Rheumatology Department, IIS-Fundación Jiménez Díaz UAM, 28040 Madrid, Spain.
Int J Mol Sci. 2023 Aug 24;24(17):13181. doi: 10.3390/ijms241713181.
Sarcopenia is a frequent comorbidity of rheumatoid arthritis (RA). Clinical trials have shown that JAK inhibitors (JAKi) produce an asymptomatic increase in serum creatine kinase (CK) in RA, suggesting an impact on muscle. We evaluated the effect of JAKi in muscle remodeling in an experimental RA model. Antigen-induced arthritis (experimental RA, e-RA) was performed in 14 rabbits. Seven rabbits received tofacitinib (TOFA, orally 10 mg/kg/day). Animals were euthanized one day after the last ovalbumin injection, and muscles were prepared for histology, RT-PCR, and WB. C-reactive protein (CRP) and Myostatin (MSTN) serum concentration were determined by ELISA. Creatine and creatine kinase (CK) were analyzed. An increase in body weight as well as tibialis anterior cross-sectional area and diameter was observed in e-RA+TOFA vs. e-RA. e-RA decreased type II fibers and increased the myonuclei number, with all reverted by TOFA. TOFA did not modify CRP levels, neither did MSTN. TOFA significantly reduced IL-6, atrogin-1, and MuRF-1 compared with e-RA. e-RA+TOFA showed higher CK and lower creatine levels compared with e-RA. No differences in PAX-7 were found, while TOFA prevented the increase in MyoD1 in e-RA. Our model reflects the features of rheumatoid sarcopenia in RA. JAKi increased muscle mass through attenuating IL-6/JAK/STAT activation, decreasing atrogenes, and restoring muscle differentiation markers. These data together with an increase in CK support the role of CK as a valuable marker of muscle gain following JAKi treatment.
肌肉减少症是类风湿关节炎（RA）的常见合并症。临床试验表明，JAK 抑制剂（JAKi）在 RA 中会导致血清肌酸激酶（CK）无症状升高，表明其对肌肉有影响。我们在实验性 RA 模型中评估了 JAKi 对肌肉重塑的影响。在 14 只兔子中进行了抗原诱导的关节炎（实验性 RA，e-RA）。7 只兔子接受托法替尼（TOFA，口服 10mg/kg/天）治疗。最后一次卵白蛋白注射后一天处死动物，并准备肌肉进行组织学、RT-PCR 和 WB 分析。通过 ELISA 测定 C 反应蛋白（CRP）和肌肉生长抑制素（MSTN）的血清浓度。分析肌酸和肌酸激酶（CK）。与 e-RA 相比，e-RA+TOFA 体重增加，胫骨前肌横截面积和直径增加。e-RA 减少 II 型纤维并增加肌核数量，所有这些都被 TOFA 逆转。TOFA 不改变 CRP 水平，也不改变 MSTN。TOFA 与 e-RA 相比，显著降低了 IL-6、atrogin-1 和 MuRF-1。与 e-RA 相比，e-RA+TOFA 显示 CK 升高，肌酸降低。PAX-7 无差异，而 TOFA 可防止 e-RA 中 MyoD1 的增加。我们的模型反映了 RA 中 RA 肌肉减少症的特征。JAKi 通过抑制 IL-6/JAK/STAT 激活、减少肌萎缩蛋白和恢复肌肉分化标志物来增加肌肉质量。这些数据以及 CK 的增加支持 CK 作为 JAKi 治疗后肌肉增加的有价值标志物的作用。
