Sepsis-induced myopathy in aging: influence of disuse on skeletal muscle regeneration

项目摘要 脓毒症是由宿主对感染的反应失调引起的危及生命的器官功能障碍的状况 并且具有高死亡风险，特别是在老年人中。尽管住院死亡率下降， 早期识别和积极的重症监护病房（ICU）管理，迅速增加的“败血症”数量 幸存者”经历持续和严重的骨骼肌无力和萎缩（即脓毒症诱导的 肌病）。这些患者经常经历长时间的卧床休息，这可能会影响他们的健康。 肌病由于未知的原因，这些患者的骨骼肌永远不会恢复到脓毒症前的功能 条件健康的骨骼肌具有很强的再生能力，这种再生能力是由一群 卫星细胞（SC）。SC位于肌膜和基底膜之间， 在所谓的SC中， 利基我们已经证明，在脓毒症中，SC失去了再生肌纤维的能力，这是一种已知的反应， 发生在衰老的过程中。我们还发现，脓毒症诱导SC的表观遗传变化， 与功能丧失有关。我们的初步观察确定了已知的循环趋化因子 在败血症和衰老中升高将健康的SC暴露于这种脓毒血清导致肌源性细胞的丧失。 容量脓毒症、衰老和骨骼肌废用共同作用的机制， 老年人的持续性肌病和再生失败仍不清楚。我们将测试 假设当面临严重的脓毒症免疫应激时，除了衰老和废用之外， 至关重要的驻留细胞不能促进肌肉功能的完全恢复。我们将测试这个 有两个具体目标的假设。主要从临床观察和我们未发表的初步研究中得出 数据，我们将结合联合收割机与后肢悬吊的经典脓毒症模型，然后重新加载，以1）测试 废用加重骨骼肌功能障碍并通过卫星细胞功能障碍阻碍修复假说 在老年脓毒症宿主中;和2）确定来自老年脓毒症宿主的卫星细胞的表观遗传特征， 趋化因子受体对这些信号的作用。我们预计，这项研究将导致一个新的临床前 模型研究脓毒症引起的肌病在老龄化。老年人干细胞表观遗传标记的鉴定 脓毒症宿主将揭示表观遗传修饰剂的治疗靶点以减轻肌病。在适当的时候，这 可以使大量在进入ICU后肌肉功能恶化的老年人受益 并且可能适用于暴露于其他类型感染的老年患者，例如受 新冠肺炎疫情。

PROJECT SUMMARY Sepsis is a condition of life-threatening organ dysfunction caused by a dysregulated host response to infection and carries a high risk of mortality, especially among older adults. Despite decreasing in-hospital mortality due to early recognition and aggressive intensive care unit (ICU) management, a rapidly growing number of “sepsis survivors” experience persistent and severe skeletal muscle weakness and atrophy (i.e. sepsis-induced myopathy). These patients often experience prolonged periods of bed rest, which possibly worsens the myopathy. For unknown reasons, the skeletal muscles of these patients never return to their pre-septic functional condition. Healthy skeletal muscles possess a great regenerative capacity that is regulated by a populations of resident cells known as satellite cells (SCs). SCs are localized between the muscle membrane and the basal lamina and are exposed to other cells and their secretory products, including chemokines, in the so called SC niche. We have shown that SCs lose their ability to regenerate muscle fibers in sepsis, a response that is known to occur in the process of aging. We have also shown that sepsis induces epigenetic changes in the SCs that are associated with the loss of function. Our preliminary observations identified circulatory chemokines known to be elevated in sepsis and aging. Exposure of healthy SCs to this septic serum resulted in a loss of myogenic capacity. The mechanisms by which the combination of sepsis, aging and skeletal muscle disuse contributes to the persistent myopathy and failure to regenerate in older adults remain unknown. We will test the overarching hypothesis that when faced with severe immunological stress of sepsis, on top of aging and disuse, these critically important resident cells are unable to facilitate complete recovery of muscle function. We will test this hypothesis with two specific aims. Drawing largely from clinical observations and our unpublished preliminary data we will combine a classic model of sepsis with hindlimb suspension followed by reloading to 1) test the hypothesis that disuse aggravates skeletal muscle dysfunction and hampers repair via satellite cell dysfunction in aged septic hosts; and 2) determine the epigenetic signatures of satellite cells from aged septic hosts and the role of chemokine receptors on these signatures. We anticipate that this study will result in a novel pre-clinical model to study sepsis-induced myopathy in aging. The identification of epigenetic signatures in SCs of aged septic hosts will reveal therapeutic targets for epigenetic modifiers to attenuate the myopathy. In due course, this can benefit a substantial number of older adults who have worsened muscle function after admission to the ICU and may be applicable for older patients who are exposed to other types of infections, such as those affected by the current COVID-19 pandemic.