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.

项目摘要 败血症是由失调的宿主对感染反应引起的威胁生命的器官功能障碍的条件 并具有高死亡率的高风险，尤其是老年人。 早期认可和积极的重症监护病房（ICU）管理，迅速增长的“败血症” 幸存者“经验”持续和严重的肌肉虚弱的弱点（即败血症诱导的 肌病）这些患者经常经历长时间的休息时间 肌病。 状况。 被称为卫星细胞（SCS）的驻留细胞。 在所谓的SC中，薄片并暴露于其他细胞和分泌产物（包括趋化因子） 利基市场。 在衰老过程中，我们还表明败血症会引起SC中的表观遗传变化 与功能的丧失有关。 在败血症和衰老中升高。 Capace。 在老年人中，坚持不懈的再生是未知的。 脸部面部的假设具有败血症的严重免疫学压力，在衰老和废药之上。 至关重要的居民细胞是促进肌肉功能的完全恢复。 假设有两个特定的目的。 数据我们将通过重新加载到1）测试您的败血症的经典模型与后肢悬架结合 通过卫星细胞功能障碍，可以使骨骼肌功能障碍加重并修复骨骼肌肉功能障碍的假设 在老化的化粪池宿主中； 趋化因子受体在签名中的作用。 研究败血症的模型在衰老中诱导的肌病。 化粪池宿主将使表观基因修饰剂在适当的时候减轻肌病 可以使大量老年人受益于对ICU的肌肉功能恶化的老年人 并且可能适用于暴露于其他类型的无情的老年患者，例如受 当前的COVID-19大流行。