Idiopathic inflammatory myopathy (commonly known as myositis) is a group of immune-related diseases characterized by muscle damage, weakness, and fatigue with unknown causes. Although overactivated innate immunity is a widely believed cause of myositis onset, the mechanism that provokes and maintains a high immune response in myositis patients is still unclear. This study aims to test if brain-derived neurotrophic factor (BDNF) deficiency per se is sufficient to cause myositis and determine its underlying mechanism. We found that ablating BDNF production in skeletal muscle is sufficient to trigger myositis development in mice. Muscle-specific Bdnf knockout (MBKO) mice displayed extensive myocyte necrosis, mononuclear cell infiltration, and myophagocytosis. In association with these damages, elevated production of pro-inflammatory cytokines such as interleukin (IL) 23, IL-1β, IL-18, and tumor necrosis factor α (TNFα) was found in the muscle of MBKO mice. Disruption of sarcolemma integrity was also detected in MBKO mice, which is a result of necroptosis executioner Mixed lineage kinase domain-like protein (MLKL) and pyroptosis executioner Gasdermin D (GSDMD) activation. Mechanistically, diminishing BDNF synthesis in myotubes enhances the accumulation of mitochondrial reactive oxygen species (mtROS), which sensitizes the cells towards TNFα-induced receptor-interacting protein kinase (RIPs) activation and promotes the formation of NLR family pyrin domain containing 3 (NLRP3)-containing inflammasome. BDNF deficiency-induced cell death could be alleviated by scavenging mtROS, suppressing the activity of GSDMD, or inhibiting receptor-interacting kinase 3 (RIP3). Similarly, supplementation of BDNF mimetics, suppression of RIP3 activity, increasing the intramyocellular antioxidant, or enhancing mitophagy ameliorated the myopathies of MBKO mice and improved their muscle strength. Together, our study demonstrates that insufficient BDNF production in mouse muscle causes the development of pathological features of myositis via enhancing oxidative stress, necroptosis, and pyroptosis in myofibers.

中文翻译：

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肌肉产生的脑源性神经营养因子缺乏通过活性氧介导的坏死性凋亡和焦亡导致炎性肌病


特发性炎症性肌病（俗称肌炎）是一组以肌肉损伤、无力和原因不明的疲劳为特征的免疫相关疾病。尽管过度激活的先天免疫是肌炎发病的一个广泛原因，但在肌炎患者中引发和维持高免疫反应的机制仍不清楚。本研究旨在测试脑源性神经营养因子 （BDNF） 缺乏症本身是否足以引起肌炎并确定其潜在机制。我们发现消融骨骼肌中 BDNF 的产生足以触发小鼠肌炎的发展。肌肉特异性 Bdnf 敲除 （MBKO） 小鼠表现出广泛的肌细胞坏死、单核细胞浸润和肌吞噬作用。与这些损伤相关，在 MBKO 小鼠的肌肉中发现促炎细胞因子如白细胞介素 （IL） 23 、 IL-1β 、 IL-18 和肿瘤坏死因子 α （TNFα） 的产生增加。在 MBKO 小鼠中也检测到肌膜完整性的破坏，这是坏死性凋亡执行者混合谱系激酶结构域样蛋白 （MLKL） 和焦亡执行者 Gasdermin D （GSDMD） 激活的结果。从机制上讲，肌管中 BDNF 合成的减少增强了线粒体活性氧 （mtROS） 的积累，这使得细胞对 TNFα 诱导的受体相互作用蛋白激酶 （RIP） 激活敏感，并促进 NLR 家族 pyrin 结构域的形成包含 3 （NLRP3） 的炎性小体。BDNF 缺陷诱导的细胞死亡可以通过清除 mtROS、抑制 GSDMD 活性或抑制受体相互作用激酶 3 （RIP3） 来缓解。 同样，补充 BDNF 模拟物、抑制 RIP3 活性、增加肌细胞内抗氧化剂或增强线粒体自噬可改善 MBKO 小鼠的肌病并提高其肌肉力量。总之，我们的研究表明，小鼠肌肉中 BDNF 产生不足通过增强肌纤维中的氧化应激、坏死性凋亡和焦亡导致肌炎病理特征的发展。