N ‐acetylcysteine attenuates the decline in muscle Na + ,K + ‐pump activity and delays fatigue during prolonged exercise in humans

Reactive oxygen species (ROS) have been linked with both depressed Na + ,K + ‐pump activity and skeletal muscle fatigue. This study investigated N ‐acetylcysteine (NAC) effects on muscle Na + ,K + ‐pump activity and potassium (K + ) regulation during prolonged, submaximal endurance exercise. Eight well‐trained subjects participated in a double‐blind, randomised, crossover design, receiving either NAC or saline (CON) intravenous infusion at 125 mg kg −1 h −1 for 15 min, then 25 mg kg −1 h −1 for 20 min prior to and throughout exercise. Subjects cycled for 45 min at 71%, then continued at 92% until fatigue. Vastus lateralis muscle biopsies were taken before exercise, at 45 min and fatigue and analysed for maximal in vitro Na + ,K + ‐pump activity (K + ‐stimulated 3‐O‐methyfluorescein phosphatase; 3‐O‐MFPase). Arterialized venous blood was sampled throughout exercise and analysed for plasma K + and other electrolytes. Time to fatigue at 92% was reproducible in preliminary trials ( c.v. 5.6 ± 0.6%) and was prolonged with NAC by 23.8 ± 8.3% (NAC 6.3 ± 0.5 versus CON 5.2 ± 0.6 min, P < 0.05). Maximal 3‐O‐MFPase activity decreased from rest by 21.6 ± 2.8% at 45 min and by 23.9 ± 2.3% at fatigue ( P < 0.05). NAC attenuated the percentage decline in maximal 3‐O‐MFPase activity (%Δactivity) at 45 min ( P < 0.05) but not at fatigue. When expressed relative to work done, the %Δactivity‐to‐work ratio was attenuated by NAC at 45 min and fatigue ( P < 0.005). The rise in plasma [K + ] during exercise and the Δ[K + ]‐to‐work ratio at fatigue were attenuated by NAC ( P < 0.05). These results confirm that the antioxidant NAC attenuates muscle fatigue, in part via improved K + regulation, and point to a role for ROS in muscle fatigue.