Richard Debigaré

An Official American Thoracic Society/European Respiratory Society Statement: Update on Limb Muscle Dysfunction in Chronic Obstructive Pulmonary Disease

BACKGROUND Limb muscle dysfunction is prevalent in chronic obstructive pulmonary disease (COPD) and it has important clinical implications, such as reduced exercise tolerance, quality of life, and even survival. Since the previous American Thoracic Society/European Respiratory Society (ATS/ERS) statement on limb muscle dysfunction, important progress has been made on the characterization of this problem and on our understanding of its pathophysiology and clinical implications. PURPOSE The purpose of this document is to update the 1999 ATS/ERS statement on limb muscle dysfunction in COPD. METHODS An interdisciplinary committee of experts from the ATS and ERS Pulmonary Rehabilitation and Clinical Problems assemblies determined that the scope of this document should be limited to limb muscles. Committee members conducted focused reviews of the literature on several topics. A librarian also performed a literature search. An ATS methodologist provided advice to the committee, ensuring that the methodological approach was consistent with ATS standards. RESULTS We identified important advances in our understanding of the extent and nature of the structural alterations in limb muscles in patients with COPD. Since the last update, landmark studies were published on the mechanisms of development of limb muscle dysfunction in COPD and on the treatment of this condition. We now have a better understanding of the clinical implications of limb muscle dysfunction. Although exercise training is the most potent intervention to address this condition, other therapies, such as neuromuscular electrical stimulation, are emerging. Assessment of limb muscle function can identify patients who are at increased risk of poor clinical outcomes, such as exercise intolerance and premature mortality. CONCLUSIONS Limb muscle dysfunction is a key systemic consequence of COPD. However, there are still important gaps in our knowledge about the mechanisms of development of this problem. Strategies for early detection and specific treatments for this condition are also needed.

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.

Optimizing pulmonary rehabilitation in chronic obstructive pulmonary disease - practical issues: A Canadian Thoracic Society Clinical Practice Guideline

Pulmonary rehabilitation (PR) participation is the standard of care for patients with chronic obstructive pulmonary disease (COPD) who remain symptomatic despite bronchodilator therapies. However, there are questions about specific aspects of PR programming including optimal site of rehabilitation delivery, components of rehabilitation programming, duration of rehabilitation, target populations and timing of rehabilitation. The present document was compiled to specifically address these important clinical issues, using an evidence-based, systematic review process led by a representative interprofessional panel of experts. The evidence reveals there are no differences in major patient-related outcomes of PR between nonhospital- (community or home sites) or hospital-based sites. There is strong support to recommend that COPD patients initiate PR within one month following an acute exacerbation due to benefits of improved dyspnea, exercise tolerance and health-related quality of life relative to usual care. Moreover, the benefits of PR are evident in both men and women, and in patients with moderate, severe and very severe COPD. The current review also suggests that longer PR programs, beyond six to eight weeks duration, be provided for COPD patients, and that while aerobic training is the foundation of PR, endurance and functional ability may be further improved with both aerobic and resistance training.

In vitro and in vivo contractile properties of the vastus lateralis muscle in males with COPD

Peripheral muscle weakness is common in chronic obstructive pulmonary disease (COPD) but it is still under debate whether weakness is due to atrophy or contractile dysfunction. In vitro and in vivo contractile properties of the vastus lateralis muscle were studied in 16 patients with stable COPD (forced expiratory volume in one second 39±16% of predicted, age 67±4 yrs (mean±sd)) and nine sedentary control subjects. Isometric knee extensor strength was measured while mid-thigh muscle cross-sectional area (MTMCSA) was obtained using computed tomography. Muscle strips from the vastus lateralis obtained through open biopsy were rapidly suspended in an oxygenated Krebs-Ringer solution that was maintained at 35°C with a pH of 7.40 to study their contractile properties. The isometric knee extensors strength/MTMCSA ratio was 0.50±0.08 versus 0.58±0.06 kg·cm−2 for COPD and control subjects, respectively. The muscle bundle cross-sectional area (CSA) was 4.6±2.1 and 4.4±3.1 mm−2, the length at which active tension was maximum was 15±4 and 15±3 mm, and maximal isometric peak forces normalised for CSA were 4.3±2.7 and 4.8±2.6 N·cm−2 for COPD and control subjects, respectively. The force/frequency relationship tended to be shifted to the right in patients with COPD, meaning that a higher stimulation frequency was necessary to produce the same relative force. Patients with COPD had a lower proportion of type I fibre than controls (26±12% versus 39±11%) with reciprocal significant increase in type IIb fibre proportion (20±16% versus 8±4%). The proportion of type IIa fibres was similar between the two groups. These results suggest that the contractile properties of the vastus lateralis are preserved in patients with chronic obstructive pulmonary disease. Therefore, the reduction in the quadriceps strength in patients with chronic obstructive pulmonary disease cannot be explained on the basis of an alteration of the contractile apparatus.

Adaptation of the diaphragm and the vastus lateralis in mild-to-moderate COPD

The chronology of diaphragm and vastus lateralis adaptation in chronic obstructive pulmonary disease (COPD) has not been studied. The hypothesis of this study was that muscle changes would occur earlier in the diaphragm than in the vastus lateralis in COPD, a finding that would suggest that local factors would be more important than systemic factors in determining the muscle phenotypic expression, at least in mild-to-moderate disease. The adaptation of the vastus lateralis and diaphragm muscles was evaluated in patients with mild-to-moderate COPD and in subjects with normal pulmonary function. In both groups, the oxidative potential and the number of lipofuscin inclusions were higher in the diaphragm than in the vastus lateralis. Compared to control, the diaphragm in COPD had a higher oxidative capacity and a higher proportion of type I fibres, with a reciprocal decrease in type IIA fibres, while there was no difference in diaphragmatic cross sectional areas, capillarisation and lipofuscin inclusions. No significant differences were found in the vastus lateralis from both groups. In conclusion, these data indicate that the diaphragm in controls and in chronic obstructive pulmonary disease has a higher oxidative potential than the vastus lateralis, and that muscle adaptation occurs earlier in the diaphragm than in the vastus lateralis in mild-to-moderate chronic obstructive pulmonary disease.

Comparative assessment of the quadriceps and the diaphragm in patients with COPD

Chronic obstructive pulmonary disease (COPD) and other chronic diseases such as heart failure are accompanied by skeletal muscle alterations that further enhance morbidity and mortality in affected individuals. Several studies have highlighted important structural and biochemical modifications in limb and respiratory muscles in COPD. Reviewing the similarities and differences between the two most studied muscles in COPD, the quadriceps and the diaphragm, may be helpful in providing important clues about the mechanisms underlying muscle changes associated with this disease. Although oxidative stress is present in both muscles, other muscle alterations are clearly distinct between the quadriceps and the diaphragm. For example, the oxidative metabolism varies in opposite directions, the diaphragm exhibiting increased resistance to fatigue while the quadriceps in COPD is characterized by premature fatigability. Differences in muscle phenotypic expression between the diaphragm and the quadriceps indicate that, in addition to systemic factors, the local microenvironment must participate in the reorganization seen in these two skeletal muscles in COPD.

Influence of work rate incremental rate on the exercise responses in patients with Copd

PURPOSE The peak work rate (Wpeak) measured during a progressive stepwise exercise test is commonly used to select the target training intensity for an exercise training program. In healthy subjects, a greater Wpeak is achieved when a faster rate of increase in work rate is used, whereas VO2 peak is independent of the rate of increase in work rate. This effect might be even more pronounced in chronic obstructive pulmonary disease (COPD) patients, in whom the VO2 kinetics during exercise are slower compared with healthy subjects. METHODS To investigate this, we studied 10 COPD patients (9 M/1 F, age: 65+/-5 yr [mean +/- SD], FEV1: 33+/-8%). They underwent, on separate days, three stepwise exercise tests on an ergocycle. For each test, increments of 5, 10, or 20 W x min(-1) were used in random order; the investigator was blinded as to which increment was used. VO2, VCO2, heart rate (HR), minute ventilation (VE), breathlessness and leg fatigue at rest, at each work rate, and at maximal capacity were obtained. RESULTS Wpeak averaged 40+/-13, 53+/-14, and 66+/-19 W for the 5-, 10-, and 20-W protocol, respectively (P < 0.001), whereas VO2 peak was comparable at 0.96+/-0.16, 1.02+/-0.18, and 1.03+/-0.20 L x min(-1). As the rate of increase in work rate became faster, the VO2/work rate relationship shifted to the right. This is exemplified by the VO2 at 40 W, which averaged 0.98+/-0.06, 0.90+/-0.09, and 0.83+/-0.10 L x min(-1) for the 5-, 10-, and 20-W protocol, respectively (P < 0.05). Similar observations were made for the relationship between HR, VE, and symptom scores, and work rate. There was no significant differences in peak values for HR and VE, and symptoms scores. CONCLUSIONS We conclude that the work rate incremental rate influences the Wpeak achieved, whereas the peak values for VO2, HR, VE, and symptom scores remain comparable. These findings have practical implications for the exercise evaluation of patients with COPD.

Autophagy in locomotor muscles of patients with chronic obstructive pulmonary disease

RATIONALE Locomotor muscle atrophy develops in patients with chronic obstructive pulmonary disease (COPD) partly because of increased protein degradation by the ubiquitin-proteasome system. It is not known if autophagy also contributes to protein degradation. OBJECTIVES To investigate whether autophagy is enhanced in locomotor muscles of stable patients with COPD, to quantify autophagy-related gene expression in these muscles, and to identify mechanisms of autophagy induction. METHODS Muscle biopsies were obtained from two cohorts of control subjects and patients with COPD and the numbers of autophagosomes in the vastus lateralis and tibialis anterior muscles, the levels of LC3B protein lipidation, and the expression of autophagy-related genes were measured in the vastus lateralis muscle. To investigate potential pathways that might induce the activation of autophagy, measures were taken of protein kinase B (AKT), mTORC1, and AMPK pathway activation, transcription factor regulation, proteasome activation, and oxidative stress. MEASUREMENTS AND MAIN RESULTS Autophagy is enhanced in the locomotor muscles of patients with COPD as shown by significantly higher numbers of autophagosomes in affected muscles as compared with control subjects. Autophagosome number inversely correlates with FEV1. In the vastus lateralis, LC3B protein lipidation is increased by COPD and the expression of autophagy-related gene expressions is up-regulated. LC3B lipidation inversely correlates with thigh cross-sectional area, FEV1, and FEV1/FVC ratio. Enhanced autophagy is associated with activation of the AMPK pathway and FOXO transcription factors, inhibition of the mTORC1 and AKT pathways, and the development of oxidative stress. CONCLUSIONS Autophagy is significantly enhanced in locomotor muscles of stable patients with COPD. The degree of autophagy correlates with severity of muscle atrophy and lung function impairment.

Feasibility and efficacy of home exercise training before lung volume reduction.

BACKGROUND Exercise training is recommended before lung volume reduction surgery (LVRS) in patients with emphysema. Unfortunately, many of these patients are referred from remote areas where there is no available rehabilitation program. The authors evaluated the feasibility and efficacy of a minimally supervised home-based exercise training program. METHODS Twenty-three emphysematous patients (age 61 +/- 6, forced expiratory volume in 1 second = 29 +/- 7% predicted [mean +/- SD]) were recruited from our LVRS program. Measurements of pulmonary function, maximal and submaximal exercise capacity, 6-minute walking distance (6-MWD), muscle strength, and quality of life with the Chronic Respiratory Questionnaire were obtained before and after training. Home-based exercise training program included muscle exercises and aerobic training, and started with detailed teaching while the follow-up was ensured through weekly phone calls and a diary filled by each patient. RESULTS Significant increases in 6-MWD (P < 0.001), quality of life (P < 0.005), peak work rate (P < 0.05), peak oxygen consumption (P < 0.05), endurance time (P < 0.005), and muscle strength were observed in the home-based exercise training program. CONCLUSIONS Home-based exercise training for patients in preparation for LVRS was feasible, and induced significant improvement in exercise tolerance and quality of life.

Profiling of mRNA Expression in Quadriceps of Patients with COPD and Muscle Wasting

Peripheral muscle wasting is a feature of chronic obstructive pulmonary disease (COPD). Potent therapeutic strategies are needed to improve peripheral muscle mass in these patients. We hypothesized that the evaluation of the mRNA expression profile of quadriceps muscle could be useful in identifying key biochemical pathways involved in the wasting process. We monitored mRNA expression profile of quadriceps muscle in four patients with COPD with muscle atrophy (age: 71.3 ± 2.1 years, mean SD; FEV1 28.3 ± 10.8 % predicted) and four control subjects (age: 66.5 ± 1.3 years) using HuU95v2 gene chips. Fifty-seven mRNAs transcripts (0.5%) were found to be differentially expressed in muscles of COPD patients (i.e., p < 0.01). Among them, forkhead box O -1 and -3 and insulin-like growth factor-1 expressions being significantly elevated in COPD subjects. Concomitantly, a significant reduction in mRNA expression of two myofilament proteins was observed. Energy production appears to be impaired as indicated by the significant rise in nicotinamide N-methyltransferase mRNA expression. This study provides for the first time evidence that genes are selectively expressed in limb muscles of COPD patients and further research need to focus on their functional roles in the pathogenesis of muscle dysfunction.