Effects of N-acetylcystein on Muscle Fatigue in ESRD

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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.