Chronic muscle weakness in sepsis survivors

脓毒症幸存者的慢性肌肉无力

• 批准号: 9426752
• 负责人: Hiroshi Saito
• 金额: $ 29.07万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9426752
• 关键词: Acute; Animal Model; Antibiotics; Antioxidants; Atrophic; Bacterial Infections; Chronic; Defect; Development; Electron Microscopy; Exhibits; Functional disorder; Goals; Histologic; Hospitals; Incidence; Individual; Infection; Inflammation; Innate Immune Response; Kinetics; Knowledge; Life; Life Style; Liquid substance; Mitochondria; Mitochondrial Proteins; Modeling; Molecular; Multienzyme Complexes; Mus; Muscle; Muscle Proteins; Muscle Weakness; Muscular Atrophy; Mutant Strains Mice; Oxidative Stress; Oxygen Consumption; Pathology; Patients; Phase; Phenotype; Proteins; Protocols documentation; Public Health; Quality of life; Recovery; Reporting; Resuscitation; SOD2 gene; Sepsis; Skeletal Muscle; Survivors; Testing; Therapeutic; Therapeutic Intervention; Transgenic Mice; clinically relevant; effective therapy; mitochondrial dysfunction; mortality; mouse model; muscle form; novel therapeutics; oxidative damage

ABSTRACT The objective of this project is to identify sub-cellular and molecular mechanisms of skeletal muscle dysfunction that are responsible for chronic weakness in sepsis survivors. Using the knowledge obtained, this project will elucidate potential therapeutic interventions targeting post-sepsis chronic muscle weakness. Over 1 million sepsis survivors are now discharged from the hospital every year, and a majority of these survivors report reduced quality of life due to considerable muscle weakness lasting for years after hospital discharge. However, the lack of an appropriate animal model has been a critical barrier to identifying the changes which persist long after recovery from sepsis. We recently developed a new mouse model that has enabled us to evaluate long-term muscle quality and function in severe sepsis survivors. Our preliminary studies demonstrate that sepsis-surviving mice exhibit significant skeletal muscle weakness, even after bacterial infection and inflammation are resolved and muscle mass is recovered, giving us the unique opportunity to evaluate molecular mechanisms of muscle weakness beyond the muscle wasting phenotype. Skeletal muscles from these sepsis-surviving mice also show histological abnormalities, significant nitro-oxidative damage, and profound structural and functional defects in mitochondria. These preliminary results support our central hypothesis that sepsis-induced oxidative damage causes mitochondrial dysfunction and sarcomeric protein damage, both of which remain long after sepsis recovery, and these are the major contributors to the sustained skeletal muscle weakness in sepsis survivors. Specific Aims to test the hypothesis are: (1) To determine mitochondrial damage and dysfunction in sepsis-surviving mice; (2) To investigate sarcomeric protein damage and its causal mechanisms in sepsis-surviving mice; and (3) To formulate therapeutic strategies to ameliorate post-sepsis chronic muscle weakness.

摘要 本项目的目的是确定骨骼肌的亚细胞和分子机制 导致脓毒症幸存者慢性虚弱的功能障碍。利用获得的知识， 该项目将阐明针对脓毒症后慢性肌无力的潜在治疗干预措施。超过1 现在每年有100万败血症幸存者出院，其中大多数幸存者 报告由于出院后持续数年的严重肌无力而导致生活质量下降。 然而，缺乏合适的动物模型一直是识别这些变化的关键障碍， 在脓毒症恢复后仍持续很长时间。我们最近开发了一种新的小鼠模型，使我们能够 评估严重脓毒症幸存者的长期肌肉质量和功能。我们的初步研究表明 脓毒症存活的小鼠即使在细菌感染后也表现出明显的骨骼肌无力， 炎症得到解决，肌肉质量得到恢复，这给了我们独特的机会来评估 肌肉萎缩表型以外的肌肉无力的分子机制。骨骼肌从 这些脓毒症存活的小鼠还显示出组织学异常、显著的硝基氧化损伤， 线粒体的结构和功能缺陷。这些初步结果支持我们的中心 脓毒症诱导氧化损伤导致线粒体功能障碍和肌节蛋白假说 损伤，这两者在败血症康复后很长一段时间内仍然存在，这些都是导致持续性损伤的主要因素。 败血症幸存者的骨骼肌无力。检验假设的具体目的是：（1）确定 脓毒症存活小鼠的线粒体损伤和功能障碍;（2）研究肌节蛋白损伤 及其致病机制;（3）制定治疗策略，以改善 脓毒症后慢性肌无力