Competition between Resistance Training and Inflammation in an On-Chip Skeletal Muscle Microtissue Model of Sepsis

项目摘要 慢性和急性炎症是多种疾病中骨骼肌病理学的重要贡献者。 与脓毒症相关的严重炎症对肌肉有深远的短期和长期影响。脓毒症是 其特征在于对感染的免疫反应失调，这可以改变肌肉力量的产生，消耗， 和生物能量学。脓毒症的幸存者发生持续性获得性虚弱的风险增加 综合征脓毒症中的炎症反应由促炎细胞因子的释放介导， 包括肿瘤坏死因子-α（TNF-α）和白细胞介素1 β（IL-1 β）。虽然我们知道败血症引起的 骨骼肌的变化与炎症有关，炎症是骨骼肌功能障碍的基础机制， 脓毒症还没有得到很好的理解，有一个显着的需要，以捕捉这些损害的演变， 制定有效的治疗策略。利用体外模型在人中建立马槟榔碱诱导的肌病 骨骼肌可以告知和阐明脓毒症病理学的基本机制， 有效的治疗方法。阻力训练是一种被广泛接受的重建肌肉的处方治疗方法 力量和质量。然而，恢复后阻力训练对许多脓毒症患者的长期影响很小， 患者，最近的研究表明，早期（恢复前）物理治疗可能会保留肌纤维交叉， 截面积虽然不是强度，表明需要进一步分析脓毒症的复杂演变。这 证据构成了我们假设的基石，即炎症限制了耐药性的治疗效果。 训练，这将通过以下具体目标在3D体外类器官模型中进行测试：1）建立一个 使用人SMMT捕获对促炎性反应的时间损伤的脓毒症体外模型 2）确定工程化SMMT响应于药物的收缩功能和结构的恢复; 暴露于促炎剂后的阻力训练。建议的技术创新和研究 是重要的，因为它将告知脓毒症引起的肌病的基本基础和 抵抗力训练以改善脓毒症后效应。这些结果将对未来的治疗产生积极影响。 提高脓毒症后生存者的生活质量。

PROJECT SUMMARY Chronic and acute inflammation are significant contributors to skeletal muscle pathology in multiple diseases. Severe inflammation associated with sepsis has profound short- and long-term effects on muscle. Sepsis is characterized by a dysregulated immune response to infection that can alter muscle force generation, wasting, and bioenergetics. Survivors of sepsis have increased risk for the development of persistent acquired weakness syndromes. The inflammatory response in sepsis is mediated by the release of pro-inflammatory cytokines, including tumor necrosis factor-alpha (TNF-α) and interleukin 1 beta (IL-1β). While we know that sepsis-induced changes in skeletal muscle are associated with inflammation, the mechanisms underlying muscle dysfunction in sepsis are not well understood, and there is a significant need to capture the evolution of these impairments to establish effective treatment strategies. Harnessing in vitro models of cytokine-induced myopathy in human skeletal muscle can inform and elucidate fundamental mechanisms of pathology in sepsis enabling development of effective treatments. Resistance training is a widely accepted prescriptive treatment for rebuilding muscle strength and mass. However, post-recovery resistance training has minimal long-term effects in many sepsis patients, and recent studies suggest that early (pre-recovery) physical therapy may preserve muscle fiber cross- sectional area though not strength, indicating a need for further analysis of the complex evolution of sepsis. This evidence formed the cornerstone of our hypothesis that inflammation limits the therapeutic effects of resistance training, which will be tested in a 3D in vitro organoid model through the following specific aims: 1) Establish an in vitro model of sepsis using human SMMT to capture temporal impairments in response to pro-inflammatory agents; 2) Determine recovery of contractile function and structure of engineered SMMT in response to resistance training following exposure to pro-inflammatory agents. The proposed technical innovation and study is important because it will inform the fundamental basis of sepsis-induced myopathies and the potential role of resistance training to ameliorate post-sepsis effects. These results will positively impact future treatment of sepsis and improve the quality of life of post-sepsis survivors.