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.