Annie Dubé

Functional and Muscular Effects of Neuromuscular Electrical Stimulation in Patients With Severe COPD: A Randomized Clinical Trial

BACKGROUND The mechanisms through which neuromuscular electrical stimulation (NMES) training may improve limb muscle function and exercise tolerance in COPD are poorly understood. We investigated the functional and muscular effects of NMES in advanced COPD. METHODS Twenty of 22 patients with COPD were randomly assigned to NMES (n = 12) or sham (n = 8) training in a double-blind controlled study. NMES was performed on quadriceps and calf muscles, at home, 5 days per week for 6 weeks. Quadriceps and calf muscle cross-sectional area (CSA), quadriceps force and endurance, and the shuttle-walking distance with cardiorespiratory measurements were assessed before and after training. Quadriceps biopsy specimens were obtained to explore the insulin-like growth factor-1/AKT signaling pathway (70-kDa ribosomal S6 kinase [p70S6K] , atrogin-1). RESULTS NMES training improved muscle CSA (P < .05), force, and endurance (P < .03) when compared with sham training. Phosphorylated p70S6K levels (anabolism) were increased after NMES as compared with sham (P = .03), whereas atrogin-1 levels (catabolism) were reduced (P = .01). Changes in quadriceps strength and ventilation during walking contributed independently to variations in walking distance after training (r = 0.77, P < .001). Gains in walking distance were related to the ability to tolerate increasing current intensities during training (r = 0.95, P < .001). CONCLUSIONS In patients with severe COPD, NMES improved muscle CSA. This was associated with a more favorable muscle anabolic to catabolic balance. Improvement in walking distance after NMES training was associated with gains in muscle strength, reduced ventilation during walking, and the ability to tolerate higher stimulation intensity. TRIAL REGISTRY ClinicalTrials.gov; No.: NCT00874965; URL: www.clinicaltrials.gov.

MAPK signaling in the quadriceps of patients with chronic obstructive pulmonary disease.

Muscle atrophy in chronic obstructive pulmonary disease (COPD) is associated with reduced exercise tolerance, muscle strength, and survival. The molecular mechanisms leading to muscle atrophy in COPD remain elusive. The mitogen-activated protein kinases (MAPKs) such as p38 MAPK and ERK 1/2 can increase levels of MAFbx/Atrogin and MuRF1, which are specifically involved in muscle protein degradation and atrophy. Our aim was to investigate the level of activation of p38 MAPK, ERK 1/2, and JNK in the quadriceps of patients with COPD. A biopsy of the quadriceps was obtained in 18 patients with COPD as well as in 9 healthy controls. We evaluated the phosphorylated as well as total protein levels of p38 MAPK, ERK 1/2, and JNK as well as MAFbx/Atrogin and MuRF1 in these muscle samples. The corresponding mRNA expression was also assessed by RT-PCR. Ratios of phosphorylated to total level of p38 MAPK (P = 0.02) and ERK 1/2 (P = 0.01) were significantly elevated in patients with COPD compared with controls. Moreover, protein levels of MAFbx/Atrogin showed a tendency to be greater in patients with COPD (P = 0.08). mRNA expression of p38 MAPK (P = 0.03), ERK 1/2 (P = 0.02), and MAFbx/Atrogin (P = 0.04) were significantly elevated in patients with COPD. In addition, phosphorylated-to-total p38 MAPK ratio (Pearsons r = -0.45; P < 0.05) and phosphorylated-to-total ERK 1/2 ratio (Pearsons r = -0.47; P < 0.05) were negatively associated with the mid-thigh muscle cross-sectional area. These data support the hypothesis that the MAPKs might play a role in the development of muscle atrophy in COPD.

Atrophy and hypertrophy signalling of the quadriceps and diaphragm in COPD

Background Factors involved in the regulation of muscle mass in chronic obstructive pulmonary disease (COPD) are still poorly understood. Comparing the signalisation involved in muscle mass regulation between two muscles with different levels of activation within the same subjects is an interesting strategy to tease out the impact of local (muscle activity) versus systemic factors in the regulation of muscle mass. A study was undertaken to measure and compare the protein levels of p-AKT, AKT, Atrogin-1, p-p70S6K, p-4E-BP1, p-GSK3β as well as the mRNA expression of Atrogin-1, MuRF1 and FoxO-1 in the quadriceps and the diaphragm of 12 patients with COPD and 7 controls with normal lung function. Methods Diaphragm biopsies were obtained during thoracic surgery and quadriceps samples were obtained from needle biopsies. Protein content and mRNA expression were measured by western blot and quantitative PCR, respectively. Results Increased mRNA expressions of Atrogin-1, MuRF1 and FoxO-1 were found in the quadriceps compared with the diaphragm only in patients with COPD. The quadriceps/diaphragm ratio for MuRF1 was higher in COPD. The protein level of p-p70S6K was decreased in the quadriceps compared with the diaphragm in patients with COPD. The quadriceps/diaphragm ratios of p-p70S6K and p-GSK3β were lower in patients with COPD than in controls. Conclusions These results indicate a greater susceptibility to a catabolic/anabolic imbalance favouring muscle atrophy in the quadriceps compared with the diaphragm in patients with COPD. The balance between the atrophy and hypertrophy signalling is inhomogeneous between respiratory and lower limb muscles, suggesting that local factors are likely to be involved in the regulation of muscle mass in COPD.

Preserved function and reduced angiogenesis potential of the quadriceps in patients with mild COPD

BackgroundLittle is known about limb muscle abnormalities in mild COPD. Inactivity and systemic inflammation could play a role in the development of limb muscle dysfunction in COPD. The objective of the present study was to characterize quadriceps function, enzymatic activities and morphometry, levels of plasma inflammatory markers and physical activity levels in daily life (PAdl) in patients with mild COPD (GOLD 1).MethodsMid-thigh muscle cross-sectional area (MTCSA), quadriceps strength, endurance, fiber-type distribution, capillarity, pro-angiogenesis factors (VEGF-A, angiopoietin I and II) and muscle oxidative capacity were assessed in 37 patients with mild COPD and 19 controls. Systemic inflammatory markers (CRP, IL-6, TNF-α, Fibrinogen, SP-D) and PAdl were assessed.ResultsMTCSA, quadriceps strength and endurance were not different between COPD and controls. Capillarity and muscle oxidative capacity were all preserved in mild COPD. Reduced pro-angiogenesis factor mRNA expression was seen in COPD. The level of moderately active intensity (>3 METs) was significantly lower in mild COPD and, in multiple regression analyses, the level of physical activity was a determinant of muscle oxidative capacity and capillarization. No between-group differences were found regarding muscle oxidative stress while circulating IL-6 levels were elevated in mild COPD.ConclusionsThe quadriceps muscle function was preserved in mild COPD although a reduced potential for angiogenesis was found. The reduced level of daily activities and evidence of systemic inflammation in these individuals suggest that these factors precede the development of overt limb muscle dysfunction in COPD.

Tolerance and Physiological Correlates of Neuromuscular Electrical Stimulation in COPD: A Pilot Study

Rationale Neuromuscular electrical stimulation (NMES) of the lower limbs is an emerging training strategy in patients with COPD. The efficacy of this technique is related to the intensity of the stimulation that is applied during the training sessions. However, little is known about tolerance to stimulation current intensity and physiological factors that could determine it. Our goal was to find potential physiological predictors of the tolerance to increasing NMES stimulation intensity in patients with mild to severe COPD. Methods 20 patients with COPD (FEV1 = 54±14% pred.) completed 2 supervised NMES sessions followed by 5 self-directed sessions at home and one final supervised session. NMES was applied simultaneously to both quadriceps for 45 minutes, at a stimulation frequency of 50 Hz. Spirometry, body composition, muscle function and aerobic capacity were assessed at baseline. Cardiorespiratory responses, leg discomfort, muscle fatigue and markers of systemic inflammation were assessed during or after the last NMES session. Tolerance to NMES was quantified as the increase in current intensity from the initial to the final NMES session (ΔInt). Results Mean ΔInt was 12±10 mA. FEV1, fat-free-mass, quadriceps strength, aerobic capacity and leg discomfort during the last NMES session positively correlated with ΔInt (r = 0.42 to 0.64, all p≤0.06) while post/pre NMES IL-6 ratio negatively correlated with ΔInt (r = −0.57, p = 0.001). FEV1, leg discomfort during last NMES session and post/pre IL-6 ratio to NMES were independent factors of variance in ΔInt (r2 = 0.72, p = 0.001). Conclusion Lower tolerance to NMES was associated with increasing airflow obstruction, low tolerance to leg discomfort during NMES and the magnitude of the IL-6 response after NMES. Trial Registration ClinicalTrials.gov NCT00809120