Oliver Catherine E, Carter Jonathan L, Hong James S, Xu Mingzhi, Kraus William E, Huffman Kim M, Truskey George A
Department of Biomedical Engineering, Duke University, Durham, NC, USA.
Department of Medicine, Duke University School of Medicine, Durham, NC, USA.
Commun Biol. 2025 Apr 9;8(1):583. doi: 10.1038/s42003-025-07970-8.
Rheumatoid arthritis (RA) is a chronic inflammatory disease affecting articular joints and skeletal muscle. To assess the role of cytokines upon muscle strength in RA, we developed an in vitro tissue-engineered human skeletal muscle model (myobundle). Myobundles were generated using primary skeletal muscle cells from the vastus lateralis muscle of RA patients and age-matched healthy controls. RA myobundles were more sensitive to 5 ng/mL IFN-γ, exhibiting reduced contractile force and altered contraction kinetics. Addition of IL-6 with or without IFN-γ led to a small but significant increase in striated fibers. Gene sets involved in the response to hypoxia, MTOR1 signaling, and the unfolded protein response were enriched in IFN-γ-treated RA myobundles, but not IFN-γ-treated controls. Tofacitinib increased contractile force, myosin heavy chain, and PIM1 protein levels in RA myobundles treated with IFN-γ. Thus, in RA muscle, low levels of IFN-γ selectively increase gene pathways that reduce contractile force.
类风湿性关节炎（RA）是一种影响关节和骨骼肌的慢性炎症性疾病。为了评估细胞因子在类风湿性关节炎中对肌肉力量的作用，我们建立了一种体外组织工程化人类骨骼肌模型（肌束）。使用来自类风湿性关节炎患者股外侧肌的原代骨骼肌细胞和年龄匹配的健康对照来生成肌束。类风湿性关节炎肌束对5 ng/mL干扰素-γ更敏感，表现出收缩力降低和收缩动力学改变。添加白细胞介素-6（无论是否添加干扰素-γ）导致横纹肌纤维有小幅但显著的增加。参与缺氧反应、MTOR1信号传导和未折叠蛋白反应的基因集在干扰素-γ处理的类风湿性关节炎肌束中富集，但在干扰素-γ处理的对照中未富集。托法替布增加了用干扰素-γ处理的类风湿性关节炎肌束中的收缩力、肌球蛋白重链和PIM1蛋白水平。因此，在类风湿性关节炎肌肉中，低水平的干扰素-γ选择性地增加了降低收缩力的基因通路。
