Eccentric versus conventional cycle training to improve muscle strength in advanced COPD: A randomized clinical trial.

OBJECTIVES: To compare eccentric (ECC) and conventional concentric (CON) cycle training on quadriceps muscle strength in advanced COPD. Secondary objective was to assess functional capacity. METHODS: A parallel-group, assessor-blind, randomized trial was conducted. Severe COPD patients were randomized to either an ECC (n = 13) or CON (n = 11) cycling program for 30-min, 3 times/week for 10 weeks. ECC group trained at ∼4-fold higher power than the CON group at similar relative heart rate intensity. RESULTS: Isometric and isokinetic quadriceps peak torque improved after ECC but not CON; between group difference was significant for isometric peak muscle force (p < 0.05). Peak cycling power and endurance time increased in both groups (p < 0.05). Dyspnea at peak cycling power improved only after ECC training (p < 0.05). Sensory intensity ratings of dyspnea and leg fatigue were significantly lower (p < 0.05) during ECC compared with CON at equivalent relative heart rate intensities. CONCLUSIONS: ECC could be an effective alternative and/or adjunct modality to pulmonary rehabilitation in severely ventilatory limited COPD patients.

Smoke-induced neuromuscular junction degeneration precedes the fibre type shift and atrophy in chronic obstructive pulmonary disease.

KEY POINTS: Chronic obstructive pulmonary disease (COPD) is largely caused by smoking, and patient limb muscle exhibits a fast fibre shift and atrophy. We show that this fast fibre shift is associated with type grouping, suggesting recurring cycles of denervation-reinnervation underlie the type shift. Compared to patients with normal fat-free mass index (FFMI), patients with low FFMI exhibited an exacerbated fibre type shift, marked accumulation of very small persistently denervated muscle fibres, and a blunted denervation-responsive transcript profile, suggesting failed denervation precipitates muscle atrophy in patients with low FFMI. Sixteen weeks of passive tobacco smoke exposure in mice caused neuromuscular junction degeneration, consistent with a key role for smoke exposure in initiating denervation in COPD. ABSTRACT: A neurological basis for the fast fibre shift and atrophy seen in limb muscle of patients with chronic obstructive pulmonary disease (COPD) has not been considered previously. The objective of our study was: (1) to determine if denervation contributes to fast fibre shift and muscle atrophy in COPD; and (2) to assess using a preclinical smoking mouse model whether chronic tobacco smoke (TS) exposure could initiate denervation by causing neuromuscular junction (NMJ) degeneration. Vastus lateralis muscle biopsies were obtained from severe COPD patients [n = 10 with low fat-free mass index (FFMI), 65 years; n = 15 normal FFMI, 65 years) and healthy age- and activity-matched non-smoker control subjects (CON; n = 11, 67 years), to evaluate morphological and transcriptional markers of denervation. To evaluate the potential for chronic TS exposure to initiate these changes, we examined NMJ morphology in male adult mice following 16 weeks of passive TS exposure. We observed a high proportion of grouped fast fibres and a denervation transcript profile in COPD patients, suggesting that motor unit remodelling drives the fast fibre type shift in COPD patient limb muscle. A further exacerbation of fast fibre grouping in patients with low FFMI, coupled with blunted reinnervation signals, accumulation of very small non-specific esterase hyperactive fibres and neural cell adhesion molecule-positive type I and type II fibres, suggests denervation-induced exhaustion of reinnervation contributes to muscle atrophy in COPD. Evidence from a smoking mouse model showed significant NMJ degeneration, suggesting that recurring denervation in COPD is probably caused by decades of chronic TS exposure.

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.

Addressing Assumptions for the Use of Non-invasive Cardiac Output Measurement Techniques During Exercise in COPD.

The multifactorial functional limitation of COPD increasingly demonstrates the need for an integrated circulatory assessment. In this study cardiac output (Qc) derived from non-inert (CO2-RB), inert (N2O-RB) gas rebreathing approaches and bioimpedance were compared to examine the limitations of currently available non-invasive techniques for exercise Qc determination in patients with chronic lung disease. Thirteen COPD patients (GOLD II-III) completed three constant cycling bouts at 20, 35, and 50% of peak work on two occasions to assess Qc with bioimpedance as well as using CO2-RB and N2O-RB for all exercise tests. Results showed significantly lower Qc using the N2O-RB or end-tidal CO2-derived Qc compared to the PaCO2-derived CO2-RB or the bioimpedance at rest and for all exercise intensities. End-tidal CO2-derived values are however not statistically different from those obtained using inert-gas rebreathing. This study show that in COPD patients, CO2-rebreathing Qc values obtained using PaCO2 contents which account for any gas exchange impairment or inadequate gas mixing are similar to those obtained using thoracic bioimpedance. Alternately, the lower values for N2O rebreathing derived Qc indicates the inability of this technique to account for gas exchange impairment in the computation of Qc. These findings indicate that the choice of a gas rebreathing technique to measure Qc in patients must be dictated by the ability to include in the derived computations a correction for either gas exchange inadequacies and/or a vascular shunt.

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.

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 O(2) 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.

Paced-walk and step tests to assess exertional dyspnea in COPD.

This study reports on the development and test-retest reproducibility of a modified shuttle walking and step testing protocols to assess exertional dyspnea in patients with COPD. Patients with COPD randomly performed four externally paced 3-min bouts of shuttle walking at 1.5, 2.5, 4.0 and 6.0 km x h(- 1) or stepping at constant rate of 18, 22, 26 and 32 steps x min(- 1). Walking and stepping procedures were repeated once, on a separate occasion. Ventilation, heart rate, gas exchange parameters and dyspnea Borg scores were obtained at the end of each exercise bout. Most patients completed walking or stepping at the slow and middle speed cadences but only 33% completed walking at 6.0 km x h(- 1) and 40% completed stepping at 32 steps x min(- 1). Walking and stepping at progressively faster pace caused a progressive increase in ventilation and dyspnea. Test-retest Pearson correlation coefficients for ventilation, heart rate, gas exchange parameters and dyspnea scores over the four exercise bouts, all exceeded 0.80. Intra-class correlation coefficients were at least as strong as Pearson coefficients. Bland & Altman representation showed that for repeated Borg scores, 92 and 96% of points lied within 2 SD of the mean difference between test-retest values for walking and stepping. The majority of moderate and severe COPD patients completed the 3-min shuttle waking testing at 1.5 to 4.0 km x h(- 1) and the 3-min of step testing at rates between 18 and 26 steps x min(- 1). Both field tests were highly reproducible in patients with COPD.

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.