Department of Biomedical Engineering, Duke University, Durham, NC, USA.
Sci Adv. 2021 Jan 22;7(4). doi: 10.1126/sciadv.abd9502. Print 2021 Jan.
Chronic inflammatory diseases often lead to muscle wasting and contractile deficit. While exercise can have anti-inflammatory effects, the underlying mechanisms remain unclear. Here, we used an in vitro tissue-engineered model of human skeletal muscle ("myobundle") to study effects of exercise-mimetic electrical stimulation (E-stim) on interferon-γ (IFN-γ)-induced muscle weakness. Chronic IFN-γ treatment of myobundles derived from multiple donors induced myofiber atrophy and contractile loss. E-stim altered the myobundle secretome, induced myofiber hypertrophy, and attenuated the IFN-γ-induced myobundle wasting and weakness, in part by down-regulating JAK (Janus kinase)/STAT1 (signal transducer and activator of transcription 1) signaling pathway amplified by IFN-γ. JAK/STAT inhibitors fully prevented IFN-γ-induced myopathy, confirming the critical roles of STAT1 activation in proinflammatory action of IFN-γ. Our results reveal a previously unknown mechanism of the cell-autonomous anti-inflammatory effects of muscle exercise and establish the utility of human myobundle platform for studies of inflammatory muscle disease and therapy.
慢性炎症性疾病常导致肌肉消耗和收缩功能减退。运动具有抗炎作用，但作用机制尚不清楚。本研究采用体外构建的人骨骼肌组织工程模型（“肌束”），研究运动模拟电刺激（E-stim）对干扰素-γ（IFN-γ）诱导的肌肉无力的影响。来自多个供体的肌束经慢性 IFN-γ处理后，肌纤维萎缩和收缩功能丧失。E-stim 改变了肌束的分泌组，诱导肌纤维肥大，并减轻 IFN-γ诱导的肌束消耗和无力，部分通过下调 IFN-γ放大的 JAK（Janus 激酶）/STAT1（信号转导和转录激活因子 1）信号通路。JAK/STAT 抑制剂完全阻止 IFN-γ 诱导的肌病，证实了 STAT1 激活在 IFN-γ的促炎作用中的关键作用。本研究结果揭示了肌肉运动的细胞自主抗炎作用的未知机制，并建立了人肌束平台用于研究炎症性肌肉疾病和治疗的用途。
