Mechanisms of sepsis-associated muscle stem cell dysfunction

摘要 脓毒症是重症监护环境中常见的危及生命的疾病。而 临床脓毒症管理的进步降低了急性脓毒症死亡率， 严重脓毒症幸存者发展为慢性疾病状态。事实上，许多幸存者报告说， 虚弱、呼吸困难和认知能力下降是他们脓毒症后生活中的衰弱并发症。我们 假设管理脓毒症长期影响的关键是了解脓毒症相关的 循环因子影响长寿的组织特异性干细胞的代谢状态。鉴于高发病率 脓毒症后肌肉功能障碍，我们建议初步评估急性和持续的代谢缺陷， 骨骼肌干细胞在成人骨骼肌中，卫星细胞是主要的常驻干细胞群 并且是骨骼肌修复和再生不可或缺的贡献者。自从建立了我的 独立实验室，我们已经取得了重大进展，了解如何浪费相关 因素损害卫星/肌肉干细胞（SC）生物学，我们有能力探索其机制， 脓毒性休克后肌肉功能障碍的代谢基础。这篇文章提出的大问题是， MIRA/R35的应用是：脓毒症相关因素如何影响SC功能？这一建议突出了三个 我们正在开发的项目领域，使用不同的实验和概念来解决这个中心问题， 战术首先，我们将探讨脓毒症相关的细胞因子如何调节SC代谢。我们发现那块肌肉 消瘦/恶病质相关的细胞因子可以增加参与调节能量代谢的途径 并建议确定脓毒症相关的细胞因子暴露对SC脂质代谢的影响。第二、 我们将研究脓毒症相关代谢物影响SC功能的机制。我们提出 有证据表明，浪费相关的代谢物可以拮抗干细胞分化，并提出 研究这些脓毒症代谢生物标志物中的一些也作为生物活性物质起作用的假设， 能够增强SC活化的信号分子。第三，我们将利用最先进的代谢组学 分析从鼠脓毒症模型中分离的肌肉干细胞以确定相关的代谢特征 败血症发作和恢复期延长我们发现，SC可以表现出持续的代谢改变， 急性代谢紊乱，并提出脓毒症相关的代谢紊乱损害SC 代谢网络的恢复期。这三个拟议项目领域的支持， 严格的干细胞生物学培训，马约诊所充满活力的研究和临床环境， 来自经验丰富的教师导师的持续专业支持和指导。总体而言，圆满完成 这一拟议的MIRA/R35奖将：a）促进建立一个动态的，独立的，和成本- 马约诊所以NIGMS为重点的有效初级教师研究计划，B）促进我们对以下问题的理解： 干细胞如何响应和适应脓毒症相关因素，以及c）推动长期脓毒症领域 管理进入新的和未充分探索的领域，如干细胞操作和代谢 重新编程

ABSTRACT Sepsis is a life-threatening condition commonly encountered in intensive care settings. While advancements in clinical sepsis management have lowered acute sepsis mortality rates, a growing number of severe sepsis survivors progress to chronic illness states. Indeed, many survivors report persistent muscle weakness, breathing difficulties, and cognitive decline as debilitating complications in their post-sepsis life. We hypothesize that a key to managing the long-term effect of sepsis is to understand how sepsis-associated circulating factors impact the metabolic state of long-lived, tissue specific stem cells. Given the high incidence of post-sepsis muscle dysfunction, we propose to initially evaluate acute and persistent metabolic defects in skeletal muscle stem cells. In adult skeletal muscle, satellite cells are the primary resident stem cell population and are indispensible contributors to skeletal muscle repair and regeneration. Since establishing my independent laboratory, we have made significant progress towards understanding how wasting-associated factors impair satellite/muscle stem cell (SC) biology and we are well positioned to explore the mechanistic and metabolic basis of muscle dysfunction following septic shock. The big picture question proposed in this MIRA/R35 application is: How do sepsis-associated factors impact SC function? This proposal highlights three of our developing project areas that address this central question using distinct experimental and conceptual tactics. First, we will explore how sepsis-associated cytokines modulate SC metabolism. We found that muscle wasting/cachexia-associated cytokines can augment pathways involved in regulating energetic metabolism and propose to define the effects of sepsis-associated cytokine exposure on lipid metabolism in SCs. Second, we will examine the mechanisms by which sepsis-associated metabolites impact SC function. We present evidence that wasting-associated metabolites can antagonize stem cell differentiation and propose investigating the hypothesis that some of these sepsis metabolic biomarkers also function as bioactive signaling molecules capable of augmenting SC activation. Third, we will leverage cutting edge metabolomics analyses of muscle stem cells isolated from murine sepsis models to define metabolic signatures associated with sepsis onset and extended recovery. We show that SCs can exhibit sustained metabolic alterations to acute metabolic disruptions and propose that sepsis-associated metabolic derangements compromise SC metabolic networks long into the recovery period. These three proposed project areas are supported by rigorous past training in stem cell biology, a vibrant research and clinical environment at the Mayo Clinic, and continued professional support and guidance from experienced faculty mentors. Overall, successful completion of this proposed MIRA/R35 award will: a) facilitate the establishment of a dynamic, independent, and cost- efficient NIGMS-focused junior faculty research program at the Mayo Clinic, b) advance our understanding of how stem cells respond and adapt to sepsis-associated factors, and c) drive the field of long-term sepsis management into new and underexplored areas, such as stem cell manipulation and metabolic reprogramming.