Chronic muscle weakness in sepsis survivors

脓毒症幸存者的慢性肌肉无力

基本信息

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
项目类别：
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

项目摘要

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.

抽象的该项目的目标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。利用所获得的知识，这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 现在每年有数百万脓毒症幸存者出院，其中大多数幸存者报告称，由于出院后持续数年的严重肌肉无力，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。从败血症恢复后仍持续很长时间。我们最近开发了一种新的鼠标模型，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和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超出肌肉消耗表型的肌肉无力的分子机制。骨骼肌来自这些败血症幸存的小鼠还表现出组织学异常、显着的硝基氧化损伤，以及线粒体的严重结构和功能缺陷。这些初步结果支持我们的中央脓毒症引起的氧化损伤导致线粒体功能障碍和肌节蛋白的假设损害，两者在脓毒症恢复后仍持续很长时间，并且是持续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在脓毒症存活小鼠中的因果机制； (3) 制定治疗策略以改善脓毒症后慢性肌肉无力。