A physiological increase in muscle glutathione after training is not seen in patients with chronic obstructive pulmonary disease (COPD), indicating abnormal peripheral muscle adaptations to exercise. We hypothesized that oxidative stress is primarily associated with low body mass index (BMI). Eleven patients with preserved BMI (BMI(N): 28.2 +/- 1.2 kg.m(-2)), 9 patients with low BMI (BMI(L): 19.7 +/- 0.60 kg.m(-2)) and 5 age-matched controls (26.5 +/- 0.9 kg.m(-2)) were studied before and after 8 weeks of high-intensity endurance training. Reduced glutathione (GSH) and gamma-glutamyl cysteine synthase heavy-subunit chain mRNA expression (gammaGCS-HS mRNA) were measured in the vastus lateralis. After training, exercise capacity increased (DeltaVO(2)PEAK, 13 +/- 5.2%; 10 +/- 5.6% and 15 +/- 4.3% in BMI(L), BMI(N) and controls, respectively; p < 0.05 each). GSH levels decreased in BMI(L) (from 5.2 +/- 0.7 to 3.7 +/- 0.8 nmol/mg protein, DeltaGSH -1.5 +/- 0.7 nmol/mg protein, p < 0.05); no changes were seen in BMI(N) (from 5.4 +/- 0.7 to 6.7 +/- 0.9 nmol/mg protein, DeltaGSH 1.3 +/- 0.9 nmol/mg protein), whereas GSH markedly increased in controls (from 4.6 +/- 1 to 8.7 +/- 0.4 nmol/mg protein, DeltaGSH 4.1 +/- 1 nmol/mg protein, p < 0.01). DeltaGSH in BMI(L) was different from DeltaGSH in BMI(N) and controls (p < 0.05, each). Consistent changes were observed in gammaGCS-HS mRNA expression. GSH depletion after training in BMI(L) may suggest that oxidative stress plays a key role in muscle wasting in COPD patients.