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

项目总结 脓毒症是一种由于宿主对感染的反应失调而导致的危及生命的器官功能障碍。 并且有很高的死亡风险，特别是在老年人中。尽管住院死亡率有所下降 由于早期发现和积极的重症监护病房(ICU)管理，迅速增长的“脓毒症”数量 幸存者经历持续和严重的骨骼肌无力和萎缩(即败血症引起的 肌病)。这些患者经常经历长时间的卧床休息，这可能会使 肌病。由于未知的原因，这些患者的骨骼肌永远不会恢复到败血症前的功能。 条件。健康的骨骼肌具有强大的再生能力，这种能力受一群 驻留细胞称为卫星细胞(SC)。干细胞位于肌膜和基底膜之间。 并暴露于其他细胞及其分泌产物，包括所谓的SC 利基市场。我们已经证明，在脓毒症中，干细胞失去了再生肌肉纤维的能力，这是一种已知的反应 发生在老化的过程中。我们还表明，脓毒症诱导了干细胞的表观遗传学变化， 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 在败血症和衰老时会升高。将健康的干细胞暴露在这种败血症血清中会导致肌源性丧失 容量。脓毒症、衰老和骨骼肌停用共同作用的机制 老年人的持续性肌病和再生能力仍不清楚。我们将测试最重要的 假设当面对严重的脓毒症免疫压力时，再加上衰老和停用，这些 至关重要的驻留细胞不能促进肌肉功能的完全恢复。我们将对此进行测试 有两个具体目标的假设。主要来自临床观察和我们未发表的初步研究 数据我们将结合一个典型的脓毒症模型与后肢悬吊，然后重新加载以测试1) 停用假说加重骨骼肌功能障碍并通过卫星细胞功能障碍阻碍修复 以及2)确定来自老年败血症宿主的卫星细胞的表观遗传学特征以及 趋化因子受体在这些信号上的作用。我们预计，这项研究将导致一种新的临床前 研究脓毒症所致衰老肌病的模型。老年人干细胞表观遗传特征的鉴定 败血症宿主将揭示表观遗传修饰物的治疗靶点，以减轻肌病。在适当的时候，这 可以使进入ICU后肌肉功能恶化的相当数量的老年人受益 并可能适用于接触其他类型感染的老年患者，如那些受 当前的新冠肺炎大流行。

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.