Effects of N-acetylcystein on Muscle Fatigue in ESRD

描述(由申请人提供)：肌肉功能障碍是终末期肾病(ESRD)患者的主要问题。与没有肾脏疾病的人相比，这些患者的最大运动量减少，身体表现差，自我报告的身体功能低。我们最近报道，ESRD患者在间歇性次最大收缩期间的下肢肌肉疲劳程度大约是健康久坐对照组的三倍，ESRD患者通常报告由于腿部疲劳而停止最大跑步机测试。因此，一种可以改善这一人群肌肉疲劳的治疗方法有可能增加日常生活活动中的耐力，提高生活质量。来自其他患者群体的数据表明，肌肉疲劳与心肌细胞内活性氧物种或氧化应激的产生有关，特别是在COPD患者中，运动和过度肌肉疲劳导致氧化应激程度被夸大。ESRD患者在血浆和骨骼肌中都有高水平的各种氧化应激标志物。因此，终末期肾病患者存在过度的肌肉疲劳和心肌细胞内的氧化损伤，但氧化应激和肌肉疲劳之间的直接联系尚未建立。单次大剂量抗氧化剂N-乙酰半胱氨酸的预治疗可以减轻健康个体间歇性次最大收缩时的肌肉疲劳，但这一方案与大多数患者的副作用有关。另一方面，在几项旨在减少心血管事件或降低同型半胱氨酸水平的研究中，N-乙酰半胱氨酸对终末期肾病患者的耐受性良好，研究范围从4周到平均14.5个月不等。尽管ESRD患者似乎极有可能像COPD患者一样对运动产生夸大的氧化反应，而且N-乙酰半胱氨酸治疗可以改善肌肉疲劳，但这一点从未得到测试。我们建议进行一项试点研究，具体目标如下。确定ESRD患者是否因运动而产生过度的氧化应激，以及N-乙酰半胱氨酸的短期治疗是否可以改善肌肉疲劳。

DESCRIPTION (provided by applicant): Muscle dysfunction is a major problem for patients with end-stage renal disease (ESRD). These patients have reduced maximal exercise capacity, poor physical performance, and low self-reported physical functioning compared to individuals without kidney disease. We recently reported that ESRD patients experience approximately three-fold greater muscle fatigue of the lower extremities during intermittent submaximal contractions than healthy sedentary control subjects, and patients with ESRD usually report stopping maximal treadmill testing because of leg fatigue. Thus, a treatment that could ameliorate muscle fatigue in this population has the potential to increase endurance during activities of daily living and improve quality of life. Data from other patient populations has shown that muscle fatigue is linked to generation of reactive oxygen species, or oxidative stress, within myocytes, particularly among patients with COPD, in which there is an exaggerated degree of oxidative stress in response to exercise and excessive muscle fatigue. Patients with ESRD have been shown to have high levels of various markers of oxidative stress, both in the plasma and in skeletal muscle. Thus, patients with ESRD have excessive muscle fatigue and oxidative damage within myocytes, but the direct link between oxidative stress and muscle fatigue has not been established. Pretreatment with a single large dose of the antioxidant N-acetylcysteine resulted in reduced muscle fatigue during intermittent submaximal contractions in healthy individuals, but this protocol was associated with side effects in most patients. On the other hand, N-acetylcysteine was well tolerated when administered to patients with ESRD in several studies ranging from 4 weeks to an average follow-up of 14.5 months designed to reduce cardiovascular events or decrease homocysteine levels. Although it seems highly likely that patients with ESRD have an exaggerated oxidative response to exercise similar to patients with COPD and that muscle fatigue could be improved by treatment with N-acetylcysteine, this has never been tested. We propose a pilot study with the following specific aims. To determine whether patients with ESRD generate excessive oxidative stress in response to exercise and whether muscle fatigue can be ameliorated by short-term treatment with N-acetylcysteine.