Several cellular and molecular alterations have been described in skeletal and respiratory muscles of patients with chronic obstructive pulmonary disease (COPD), but information on potential abnormalities of mitochondrial function is scarce. The aim of the present study was to investigate mitochondrial function in the vastus lateralis (VL) and external intercostalis (EI) of COPD patients. Biopsies from VL and EI were obtained during surgery for lung cancer in 13 patients with mild to moderate COPD (age 68+/-6 yrs, forced expiratory volume in one second (FEV(1)) 66+/-15% predicted) and 19 control subjects (age 67+/-9 yrs, FEV(1) 95+/-18% pred). State 3 and 4 mitochondrial oxygen consumption (V'(O(2),m)), ATP synthesis, citrate synthase, cytochrome oxidase (COX) and complex I-III activities, as well as reactive oxygen species (ROS) production, were determined. In COPD patients, in both muscles, COX activity (VL: COPD 3.0+/-0.8 versus control 2.0+/-0.8; EI: 3.7+/-1.6 versus 2.4+/-0.9 micromol min(-1) mg(-1)) and ROS production (VL: 1,643+/-290 versus 1,285+/-468; EI: 1,033+/-210 versus 848+/-288 arbitrary units) were increased, whereas state 3 V'(O(2),m) was reduced (VL: 2.9+/-0.3 versus 3.6+/-0.4; EI: 3.6+/-0.3 versus 4.1+/-0.4 mmol min(-1) kg(-1)). Skeletal muscle mitochondria of patients with chronic obstructive pulmonary disease show electron transport chain blockade and excessive production of reactive oxygen species. The concurrent involvement of both vastus lateralis and external intercostalis suggests a systemic (rather than a local) mechanism(s) already occurring in relatively early stages (Global Initiative for Chronic Obstructive Lung Disease stage II) of the disease.

We studied 21 patients with chronic obstructive pulmonary disease aged [mean (SD)] 63 (10) years, with a mean forced expiratory volume in 1 s of 40 (6)% and a peak oxygen uptake of 67 (11)% of predicted values. Patients trained for 6 weeks on a cycle ergometer at high work-rates (WR). Near-infrared spectroscopy was used to obtain the time-constant of the deoxygenation recovery signal (tauHbO(2)) during three constant WR exercise tests, one below and two above the lactic acidosis threshold (theta(L)). Glycolytic and oxidative enzymes and lactate concentrations were assessed in muscle biopsies. The tauHbO(2) decreased significantly in all three constant WR tests: -18 (24)s, -20 (23) s and -13 (22) s, respectively. Endurance time increased in the higher WR tests, by 5.7 (4.8) min and 3.6 (2.7) min, respectively. The activity of citrate-synthase (CS) and creatine-kinase changed significantly from 20 (10) to 30 (13) micro mol x min(-1) x g(-1)and from 3.825 (950) to 3.402 (526) micro mol x min(-1) x g(-1), respectively. Training also improved significantly the mean response time of the on-transient of oxygen uptake (tau'VO(2)) of the below-theta(L) test. We found significant correlations between changes in CS and changes in tauHbO(2), tau'VO(2) and endurance time. We conclude that leg training accelerates the speed of re-oxygenation of the vastus lateralis muscle after exercise. This improvement is correlated to changes in the oxidative enzymes.

Skeletal muscle dysfunction (SMD) is frequent in patients with chronic obstructive pulmonary disease (COPD). Mitochondrial abnormalities appear to play a role in the pathogenesis of SMD. The mitochondrion permeability transition pore (MPTP) facilitates the leakage of mitochondrial matrix constituents, such as cytochrome c (cyto-c), and triggers apoptosis, known to occur in skeletal muscle of patients with COPD. Our objective was to study MPTP kinetics and cyto-c release in skeletal muscle mitochondria of patients with COPD. Mitochondria were isolated from the vastus lateralis (VL), external intercostalis (EI), and latissimus dorsi (LD) in 11 patients with COPD (66 +/- 9 yr; FEV(1) 66 +/- 13%) and 15 smokers with normal lung function (64 +/- 6 yr; FEV(1) 95 +/- 11%) who required thoracic surgery for a localized lung neoplasm. MPTP kinetics were determined spectrophotometrically (time to reach V'max, V'max and mitochondrial swelling) and cyto-c release by enzyme-linked immunosorbent assay. MPTP kinetics and cyto-c release were abnormal in patients with COPD in the three muscles studied. In addition, V'max of VL mitochondria was significantly related (P < 0.01) to BMI (r = -0.75 COPD, -0.67 control) and aerobic capacity (r = -0.70 COPD, -0.60 control) for the COPD group. MPTP kinetics and cyto-c release are abnormal in skeletal and respiratory muscles of patients with moderate COPD, suggesting a systemic mechanism(s) occurring early during the course of the disease.

The purpose of the study was to characterise statistically the inherent fluctuations in breath-by-breath measurements of pulmonary gas exchange (oxygen uptake and carbon dioxide output, V*O2 and V*CO2, respectively) and pulmonary ventilation (V*E) in patients with chronic obstructive pulmonary disease (COPD) and to compare them with those of healthy control subjects. Thirty subjects with COPD [mean (SD): 67 (6) years old; forced expiratory volume in 1 min, FEV1 1.25( 0.18) l; 42 (6)% predicted FEV1] and 12 healthy subjects [31 (3) years old; FEV1 3.62 (0.54) l; 99 (8)% predicted FEV1] performed exercise tests on a cycle ergometer at a constant work rate of moderate intensity. Steady-state exercise values for V*O2, V*CO2 and V*E were 905 (96) ml.min(-1), 847(90) ml.min(-1) and 23 (3) l.min(-1), respectively for the COPD patients and 1239(89) ml.min(-1), 1191(84) ml.min(-1)and 37(3) l.min(-1), respectively, for the healthy controls. The breath-by-breath fluctuations were well characterised by a Gaussian density-probability function with breath-to-breath autocorrelations that were not significantly different from 0, up to four subsequent breaths. Its magnitude varied among variables, but was independent of the signal amplitude for the same subject and variable. With ratios of amplitude of fluctuation:signal of around 10%, typical of the patients studied, the resolution of time constants and amplitude were congruent with 9 s and congruent with 100 ml.min(-1), respectively for V*O2 or V*CO2 with one repetition.