N-acetylcysteine (NAC) is a nonspecific antioxidant that selectively i
nhibits acute fatigue of rodent skeletal muscle stimulated at low (but
not high) tetanic frequencies and that decreases contractile function
of unfatigued muscle in a dose-dependent manner. The present experime
nts test the hypothesis that NAC pretreatment can inhibit acute muscul
ar fatigue in humans. Healthy volunteers were studied on two occasions
each. Subjects were pretreated with NAC 150 mg/kg or 5% dextrose in w
ater by intravenous infusion. The subject then sat in a chair with sur
face electrodes positioned over the motor point of tibialis anterior,
an ankle dorsiflexor of mixed-fiber composition. The muscle was stimul
ated to contract electrically (40-55 mA, 0.2-ms pulses) and force prod
uction was measured. Function of the unfatigued muscle was assessed by
measuring the forces produced during maximal voluntary contractions (
MVC) of ankle dorsiflexor muscle groups and during electrical stimulat
ion of tibialis anterior at 1, 10, 20, 40, 80, and 120 Hz (protocol 1)
. Fatigue was produced using repetitive tetanic stimulations at 10 Hz
(protocol 1) or 40 Hz (protocol 2); intermittent stimulations subseque
ntly were used to monitor recovery from fatigue. The contralateral leg
then was studied using the same protocol. Pretreatment with NAC did n
ot alter the function of unfatigued muscle; MVC performance and the fo
rce-frequency relationship of tibialis anterior were unchanged. During
fatiguing contractions stimulated at 10 Hz, NAC increased force outpu
t by similar to 15% (P < 0.0001), an effect that was evident after 3 m
in of repetitive contraction (P < 0.0125) and persisted throughout the
30-min protocol. NAC had no effect on fatigue induced using 40 Hz sti
muli or on recovery from fatigue. N-acetylcysteine pretreatment can im
prove performance of human limb muscle during fatiguing exercise, sugg
esting that oxidative stress plays a causal role in the fatigue proces
s and identifying antioxidant therapy as a novel intervention that may
be useful clinically.