Jacinthe Baril

The Mitochondrial Phenotype of Peripheral Muscle in Chronic Obstructive Pulmonary Disease Disuse or Dysfunction

RATIONALE Peripheral muscle alterations have been recognized to contribute to disability in chronic obstructive pulmonary disease (COPD). OBJECTIVES To describe the mitochondrial phenotype in a moderate to severe COPD population and age-matched controls. METHODS Three primary aspects of mitochondrial function were assessed in permeabilized locomotor muscle fibers. MEASUREMENTS AND MAIN RESULTS Respiration rates per milligram of fiber weight were significantly lower in COPD muscle compared with healthy age-matched control muscle under various respiratory states. However, when variations in mitochondrial volume were taken into account by normalizing respiration per unit of citrate synthase activity, differences between the two groups were abolished, suggesting the absence of specific mitochondrial respiratory impairment in COPD. H(2)O(2) production per mitochondrion was higher both under basal and ADP-stimulated states, suggesting that mitochondria from COPD muscle have properties that potentiate H(2)O(2) release. Direct assessment of mitochondrial sensitivity to Ca(2+)-induced opening of the permeability transition pore (PTP) indicated that mitochondria from patients with COPD were more resistant to PTP opening than their counterparts in control subjects. CONCLUSIONS Comparison of these results with those of studies comparing healthy glycolytic with oxidative muscle suggests that these differences may be attributable to greater type II fiber expression in COPD muscle, as mitochondria within this fiber type have respiratory function similar to that of mitochondria from type I fibers, and yet are intrinsically prone to greater release of H(2)O(2) and more resistant to PTP opening. These results thus argue against the presence of pathological mitochondrial alterations in this category of patients with COPD.

Altered mitochondrial regulation in quadriceps muscles of patients with COPD

Evidence exists for locomotor muscle impairment in patients with chronic obstructive pulmonary disease (COPD), including fiber type alterations and reduced mitochondrial oxidative capacity. In this study high‐resolution respirometry was used to quantify oxygen flux in permeabilized fibres from biopsies of the vastus lateralis muscle in patients with COPD and compared to healthy control subjects. The main findings of this study were that (i) routine state 2 respiration was higher in COPD; (ii) state 3 respiration in the presence of ADP was similar in both groups with substrate supply of electrons to complex I (COPD 38·28 ± 3·58 versus control 42·85 ± 3·10 pmol s−1 mg tissue−1), but O2 flux with addition of succinate was lower in COPD patients (COPD 63·72 ± 6·33 versus control 95·73 ± 6·53 pmol s−1 mg tissue−1); (iii) excess capacity of cytochrome c oxidase in COPD patients was only ∼50% that of control subjects. These results indicate that quadriceps muscle mitochondrial function is altered in patients with COPD. The regulatory mechanisms underlying these functional abnormalities remain to be uncovered.

Eccentric cycle exercise in severe COPD: feasibility of application.

Eccentric cycling may present an interesting alternative to traditional exercise rehabilitation for patients with advanced COPD, because of the low ventilatory cost associated with lengthening muscle actions. However, due to muscle damage and soreness typically associated with eccentric exercise, there has been reluctance in using this modality in clinical populations. This study assessed the feasibility of applying an eccentric cycling protocol, based on progressive muscle overload, in six severe COPD patients with the aim of minimizing side effects and maximizing compliance. Over 5 weeks, eccentric cycling power was progressively increased in all patients from a minimal 10-Watt workload to a target intensity of 60% peak oxygen consumption (attained in a concentric modality). By 5 weeks, patients were able to cycle on average at a 7-fold higher power output relative to baseline, with heart rate being maintained at ∼85% of peak. All patients complied with the protocol and presented tolerable dyspnea and leg fatigue throughout the study; muscle soreness was minimal and did not compromise increases in power; creatine kinase remained within normal range or was slightly elevated; and most patients showed a breathing reserve > 15 L.min−1. At the target intensity, ventilation and breathing frequency during eccentric cycling were similar to concentric cycling while power was approximately five times higher (p = 0.02). This study showed that an eccentric cycling protocol based on progressive increases in workload is feasible in severe COPD, with no side effects and high compliance, thus warranting further study into its efficacy as a training intervention.

Eccentric Ergometer Training Promotes Locomotor Muscle Strength but Not Mitochondrial Adaptation in Patients with Severe Chronic Obstructive Pulmonary Disease

Eccentric ergometer training (EET) is increasingly being proposed as a therapeutic strategy to improve skeletal muscle strength in various cardiorespiratory diseases, due to the principle that lengthening muscle actions lead to high force-generating capacity at low cardiopulmonary load. One clinical population that may particularly benefit from this strategy is chronic obstructive pulmonary disease (COPD), as ventilatory constraints and locomotor muscle dysfunction often limit efficacy of conventional exercise rehabilitation in patients with severe disease. While the feasibility of EET for COPD has been established, the nature and extent of adaptation within COPD muscle is unknown. The aim of this study was therefore to characterize the locomotor muscle adaptations to EET in patients with severe COPD, and compare them with adaptations gained through conventional concentric ergometer training (CET). Male patients were randomized to either EET (n = 8) or CET (n = 7) for 10 weeks and matched for heart rate intensity. EET patients trained on average at a workload that was three times that of CET, at a lower perception of leg fatigue and dyspnea. EET led to increases in isometric peak strength and relative thigh mass (p < 0.01) whereas CET had no such effect. However, EET did not result in fiber hypertrophy, as morphometric analysis of muscle biopsies showed no increase in mean fiber cross-sectional area (p = 0.82), with variability in the direction and magnitude of fiber-type responses (20% increase in Type 1, p = 0.18; 4% decrease in Type 2a, p = 0.37) compared to CET (26% increase in Type 1, p = 0.04; 15% increase in Type 2a, p = 0.09). EET had no impact on mitochondrial adaptation, as revealed by lack of change in markers of mitochondrial biogenesis, content and respiration, which contrasted to improvements (p < 0.05) within CET muscle. While future study is needed to more definitively determine the effects of EET on fiber hypertrophy and associated underlying molecular signaling pathways in COPD locomotor muscle, our findings promote the implementation of this strategy to improve muscle strength. Furthermore, contrasting mitochondrial adaptations suggest evaluation of a sequential paradigm of eccentric followed by concentric cycling as a means of augmenting the training response and attenuating skeletal muscle dysfunction in patients with advanced COPD.

Comparison of Respiratory and Circulatory Responses to 1-Leg, 2-Leg Knee Extension Exercise and Cycling in Patients with COPD

Background: The mass-specific work rates at which peripheral circulatory blood flow (BF) may become compromised in COPD due to a “respiratory steal” phenomenon was examined using one leg (1-leg KE), two-leg knee extension (2-leg KE) and cycling. Methods: Eleven COPD patients (age: 66 yr ± 8; FEV1= 45% predicted ± 14) did three steady states of cycling, 1-leg KE and 2-leg KE at 20, 40 and 65% of peak power (SS20%; SS40%; SS65%). Ventilation, VO2, arterial blood gas and dye dilution cardiac output were measured at rest and during exercise. Inspiratory capacity (IC) was used to monitor operating lung volume responses and determine dynamic hyperinflation. Results: Preliminary data show higher VO2 (L•min-1) during cycling than 1-leg KE and 2-leg KE (SS65% 1.0 ± 0.2 vs 0.5 ± 0.1 vs 0.6 ± 0.1). Despite the smaller muscle mass involvement of 1-leg KE, breathing frequency during SS65% was not different from that of cycling at SS65% (27 ± 5 vs 28 ± 5). During 1-leg KE, a plateau in tidal volume (0.8L ± 0.1) was achieved at SS20% while during cycling, tidal volume increased up to 1.4L ± 0.3 at SS65%. Similar falls in pH from baseline and similar PCO2 measures were seen with cycling (baseline: pH 7.43 ± 0.02; PaCO2 mmHg 39 ± 2 to SS65%: 7.38 ± 0.03; 40 ± 3) and 1-leg KE (baseline: pH 7.41 ± 0.03; PaCO2 mmHg 39 ± 2 to SS65%: 7.39 ± 0.02; 40 ± 3) although SaO2 was maintained with 1-leg KE, but not with cycling or 2-leg KE (95 to 93% at SS65%). IC (in % total lung capacity) was similarly reduced from baseline in 1-leg KE (30 ± 2 to 23 ± 3) and during cycling (30 ± 2 to 24 ± 3). Conclusion: These data suggest that ventilatory and gas exchange responses depend on the relative symptom-limited exercise intensity and not exercise modality.

Leg Muscle Blood Flow During 1 and 2-leg Knee Extension Exercise in Patients with COPD and Aged-Controls

Background: In chronic obstructive pulmonary disease (COPD), leg muscle blood flow may be compromised during dynamic exercise due to the competing influence of respiratory muscle work for available cardiac output. This study examined the flow demand limits of skeletal muscle flow in varying muscle mass recruitment. It employed one leg knee extension (1L-KE) and two-leg knee extension (2L-KE) to examine the mass-specific work rates at which peripheral circulatory function may become compromised due to elevated respiratory demands. Methods: Three male COPD patients (70 ± 5 yr; FEV1 /FVC = 42 ± 11%) and two aged-controls (74 ± 1 yr; FEV1/FVC = 76 ± 5%) completed three sets of 7-minute steady state 1L-KE and 2L-KE at 20, 40 and 65% (SS20%; SS40%; SS65%) of previously determined ergometer-specific peak power, separated by rest periods of 15 min. Leg muscle blood flow (BF) was determined using pulsed Doppler sonography of the femoral artery during incremental exercise loads and post-exercise. ECG, blood pressure, ventilatory parameters and VO2 were obtained continuously, and dye dilution cardiac output was measured at rest and during exercise. Results: Preliminary data showed that, for each exercise intensity, the required VO2 is similar in both groups. However, the workloads in COPD are between 60% and 82% of the control group workloads. During 1L-KE and 2L-KE, BF is consistently higher in COPD compared to controls. For 1L-KE, the increase in BF from rest (mean ± SD in ml/min; COPD vs controls) are SS20%: 763 ± 244 vs 105 ± 34; SS40%: 1157 ± 597 vs 310 ± 97; SS65%: 1493 ± 348 vs 424 ± 45. BF relative to workload is at least 3-fold higher in COPD compared to controls for all exercise intensities. Conclusions: These data suggest that mean muscle blood flow may not be compromised during knee-extensor exercise in COPD patients, and ongoing data will clarify whether this is a compensatory response to altered peripheral muscle metabolic function.