Aging and Critical Care Research Laboratory, University of Kentucky, Lexington, United States.
Department of Physiology, University of Kentucky, Lexington, United States.
Elife. 2019 Dec 3;8:e49920. doi: 10.7554/eLife.49920.
Chronic critical illness is a global clinical issue affecting millions of sepsis survivors annually. Survivors report chronic skeletal muscle weakness and development of new functional limitations that persist for years. To delineate mechanisms of sepsis-induced chronic weakness, we first surpassed a critical barrier by establishing a murine model of sepsis with ICU-like interventions that allows for the study of survivors. We show that sepsis survivors have profound weakness for at least 1 month, even after recovery of muscle mass. Abnormal mitochondrial ultrastructure, impaired respiration and electron transport chain activities, and persistent protein oxidative damage were evident in the muscle of survivors. Our data suggest that sustained mitochondrial dysfunction, rather than atrophy alone, underlies chronic sepsis-induced muscle weakness. This study emphasizes that conventional efforts that aim to recover muscle quantity will likely remain ineffective for regaining strength and improving quality of life after sepsis until deficiencies in muscle quality are addressed.
慢性危重病是一个全球性的临床问题，每年影响数以百万计的脓毒症幸存者。幸存者报告称存在慢性骨骼肌无力，并出现新的持续多年的功能障碍。为了阐明脓毒症引起的慢性虚弱的机制，我们首先通过建立一种具有 ICU 样干预措施的脓毒症小鼠模型来克服一个关键障碍，该模型允许对幸存者进行研究。我们发现，脓毒症幸存者至少有 1 个月的严重虚弱，即使在肌肉量恢复后也是如此。幸存者的肌肉中存在明显的线粒体超微结构异常、呼吸和电子传递链活性受损以及持续的蛋白质氧化损伤。我们的数据表明，慢性脓毒症引起的肌肉虚弱的基础是持续的线粒体功能障碍，而不仅仅是萎缩。这项研究强调，在解决肌肉质量缺陷之前，旨在恢复肌肉量的常规方法可能仍然无法有效恢复脓毒症后的力量和生活质量。
