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

脓毒症引起的衰老肌病：废用对骨骼肌再生的影响

• 批准号: 10413969
• 负责人: Orlando Laitano
• 金额: $ 1.93万
• 依托单位: FLORIDA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2022-08-09
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10413969
• 关键词: Acute; Admission activity; Adult; Affect; Age; Aging; Area; Atrophic; Attenuated; Basal lamina; Bed rest; Behavior; Biology of Aging; C57BL/6 Mouse; CCL2 gene; COVID-19 pandemic; CXCL1 gene; CXCL10 gene; CXCL2 gene; Cell physiology; Cells; Clinical; DNA; DNA Methylation; Data; Development; Elderly; Epigenetic Process; Exposure to; Face; Failure; Female; Fiber; Functional disorder; Genes; Goals; Health; Hindlimb Suspension; Hospital Mortality; Hospitals; Immune response; Immunologics; Impairment; Individual; Infection; Injury; Intensive Care Units; Knowledge; Leukocytes; Life; Membrane; Methylation; Modeling; Morbidity - disease rate; Mus; Muscle; Muscle Fibers; Muscle Weakness; Muscle function; Muscular Atrophy; Myopathy; Natural regeneration; Operative Surgical Procedures; Organ; Pathway interactions; Patients; Phenotype; Physiology; Population; Pre-Clinical Model; Process; Promoter Regions; Proteins; Public Health; Recovery; Regenerative capacity; Research; Rest; Role; Sepsis; Serum; Skeletal Muscle; Skeletal Muscle Satellite Cells; Skeletal muscle injury; Stress; Survivors; Testing; Time; aged; bisulfite sequencing; cecal ligation puncture; cell age; chemokine; chemokine receptor; clinical care; cohort; disability; experience; experimental study; falls; genome-wide; high risk; improved; injury recovery; loss of function; male; methylation pattern; mortality; mortality risk; muscle regeneration; new therapeutic target; novel; older patient; physical inactivity; postoperative recovery; repaired; response; satellite cell; septic; septic patients; skeletal muscle weakness; stem cells; therapeutic target; therapy development; young adult

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.

项目概要 脓毒症是一种危及生命的器官功能障碍，由宿主对感染的反应失调引起 尽管住院死亡率有所下降，但死亡风险很高，尤其是老年人。 由于早期识别和积极的重症监护病房 (ICU) 管理，“脓毒症”数量迅速增加 “幸存者”经历持续且严重的骨骼肌无力和萎缩（即脓毒症引起的 这些患者经常需要长时间卧床休息，这可能会使病情恶化。 由于未知的原因，这些患者的骨骼肌从未恢复到脓毒症前的功能。 健康的骨骼肌具有强大的再生能力，受群体调节。 称为卫星细胞 (SC) 的常驻细胞位于肌膜和基底之间。 层并暴露于其他细胞及其分泌产物，包括趋化因子，在所谓的 SC 中 我们已经证明，SCs 在脓毒症中失去了再生肌肉纤维的能力，这是一种已知的反应。 我们还发现脓毒症会引起 SC 的表观遗传变化。 我们的初步观察发现了已知的循环趋化因子。 在脓毒症和衰老过程中，健康的 SC 暴露于这种脓毒症血清中会导致肌原性丧失。 脓毒症、衰老和骨骼肌废用共同导致的机制。 老年人的持续性肌病和再生障碍仍然未知，我们将测试总体情况。 假设当面临脓毒症的严重免疫应激时，除了衰老和废用之外，这些 至关重要的驻留细胞无法促进肌肉功能的完全恢复，我们将对此进行测试。 具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结果。 数据我们将结合脓毒症的经典模型与后肢悬挂，然后重新加载以 1) 测试 假设废用会加剧骨骼肌功能障碍并通过卫星细胞功能障碍阻碍修复 在老年化脓性宿主中；2) 确定老年化脓性宿主卫星细胞的表观遗传特征和 我们预计这项研究将产生一种新的临床前研究。 研究衰老过程中败血症诱发的肌病的模型。 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。 可以使大量进入 ICU 后肌肉功能恶化的老年人受益 并且可能适用于接触其他类型感染的老年患者，例如受感染的患者 当前的 COVID-19 大流行。