Skeletal Muscle Adaptations to Interval Training in Patients With ...

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such as oxygen supplementation or continuous positive airway pressure, have been employed. 13 An alternative approach that allows high-intensity exercise to be performed for sufficiently long periods of time is interval exercise (IE). In healthy subjects with this type of exercise, it is possible to impose maximal loads on both muscles and oxygen-transporting organs without significant engagement of anaerobic processes, thus allowing a great amount of work to be performed before exhaustion sets in. 15 In patients with advanced COPD, IE training, consisting of repeated bouts of high or even maximal-intensity work separated by periods of lower intensity work or rest, has been shown to be associated with a small increase in lactate concentration, stable ventilation, and low symptoms of dyspnea and leg discomfort, thus allowing the total amount of work performed to be significantly greater than at CLE training. 16–17 In addition, application of IE training into pulmonary rehabilitation has been shown to be an equally effective alternative to moderately intense CLE training in terms of improving exercise tolerance and quality of life. 18 As there is evidence 19–20 that patients with advanced COPD have a significant metabolic reserve capacity that is only evident when muscle activity is somewhat freed from ventilatory constraints, it was hypothesized that application of high-intensity IE training in the rehabilitation of these patients would induce significant peripheral muscle adaptations leading to improvements in exercise tolerance. Consequently, the purpose of the present study was primarily to investigate the response to high-intensity IE training by specifically looking at changes in morphologic and biochemical characteristics of the vastus lateralis muscle. In addition, we compared the magnitude of peripheral muscle adaptations induced by high-intensity IE training to that incurred after implementation of the commonly applied moderately intense CLE training modality. *From the Department of Critical Care Medicine and Pulmonary Services (Drs. Nanas, Stratakos, Simoes, Zakynthinos, and Roussos), Pulmonary Rehabilitation Centre, Evangelismos Hospital, and Thorax Foundation “M. Simou and G.P. Livanos Laboratories”; Department of Physical Education and Sport Science (Drs. Terzis and Vogiatzis, and Ms. Georgiadou), National & Kapodistrian University of Athens, Athens, Greece. This work was supported in part by the European Community CARED FP5 project (No. QLG5-CT-2002–0893) and by the Thorax Foundation. Manuscript received March 4, 2005; revision accepted September 26, 2005. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal. org/misc/reprints.shtml). Correspondence to: Ioannis Vogiatzis, PhD, National & Kapodistrian University of Athens, Medical School, Thorax Foundation 3 Ploutarhou Str. 106 75, Athens, Greece; e-mail:gianvog@phed. uoa.gr Subjects Materials and Methods Patients included 16 men and 3 women with stable, advanced COPD who satisfied the following criteria: (1) postbronchodilator FEV 1 50% of predicted and FEV 1/FVC 70% without significant reversibility ( 12% change of the initial FEV 1 value), (2) optimized medical therapy, and (3) no clinical evidence of exercise-limiting cardiovascular or neuromuscular diseases. Patients signed an informed consent form that was approved by the University Ethics Committee. Study Design The study was designed as a randomized, controlled, parallel, two-group study. Once it was verified that patients met the selection criteria, they were randomly assigned to one of the two training modalities: IE or CLE. Stratified randomization was used to achieve approximate balance of certain characteristics (Table 1), including FEV 1 ( 40 or 40% of predicted) and peak work rate (Wpeak) [ 50 or 50 W] that was assessed by a ramp-incremental cycle ergometer test. Pulmonary Function Assessment Spirometry and diffusion capacity of the lung for carbon monoxide (Dlco) were performed (Masterlab; Jaeger; Wurzburg, Germany) according to recommended techniques. 21 Arterial blood gas was also analyzed at rest (ABL330; Radiometer; Copenhagen, Denmark). Rehabilitation Program The rehabilitation program was multidisciplinary and included supervised exercise training, breathing control and relaxation techniques, methods of clearance of pulmonary secretions, disease education, dietary advice, and psychological support on issues relating to chronic disability. Similarly to our previous rehabilitation study, 18 the exercise prescription was designed to present patients with a similar overall training load. Patients assigned to the IE group were instructed to exercise on electromagnetically braked cycle ergometers (Cateye Ergociser, ECl600; Cat Eye; Osaka, Japan) at an intensity initially targeted Table 1—Baseline Lung Function Characteristics Between the IE and the CLE Training Groups* Characteristics IE (n 10) CLE (n 9) Age, yr 64 3 67 2 Body mass index, 25.9 1.2 26.9 1.3 kg/m 2 FEV1, L (% predicted) 1.12 0.15 (44 6) 1.07 0.16 (39 6) FVC, L (% predicted) 2.64 0.28 (82 8) 2.67 0.27 (75 7) FEV1/FVC, % 42 4 44 6 Dlco, % predicted 51 9 47 8 IC, % predicted 71 6 71 12 Pao2,mmHg 69 6 64 4 Paco2,mmHg 39 1 41 1 pH 7.43 0.01 7.44 0.01 Arterial oxygen saturation, % 94 1 92 1 *Data are presented as mean SEM. www.chestjournal.org CHEST / 128 /6/DECEMBER, 2005 3839 Downloaded From: http://jupcvss.chestpubs.org/ on 08/01/2013
to 100% of Wpeak, assessed prior to rehabilitation by a rampincremental cycle ergometer test (see below), with 30 s of work interspersed with 30-s rest periods for 45 min/d, 3 days per week, for 10 weeks. Patients assigned to the CLE group were instructed to exercise for the same weekly frequency and total duration as the IE group but at an intensity that was initially equivalent to 60% of baseline Wpeak for 30 min each time. Therefore, at the outset of the study, the total amount of work done per session by each member of the IE group was designed to equate the work that these patients would have done had they been assigned to the CLE group. As training principles require the training intensity to parallel the improvement in physical fitness, 13 the weekly training load for the IE group was designed to represent 100% during weeks 1 to 3, 120% during weeks 4 to 6, and 140% of Wpeak during the last 4 weeks. For the CLE group, the load was designed to represent 60%, 70%, and 80% of Wpeak, respectively, for the three weekly periods. Supervision during training involved measurements of pulse oxygen saturation, heart rate, and sensation of dyspnea and leg discomfort. During training, supplemental oxygen was provided at a rate of 1.5 to 2.0 L/min in six patients in the IE group and four patients in the CLE group. Muscle Biopsy Within a week before and after the rehabilitation program, percutaneous biopsies of the right vastus lateralis muscle were performed at mid-thigh (15 cm above the patella) as described by Bengstrom. 22 Briefly after local anesthesia with 1.5 mL of lidocaine 2%, a 1-cm skin incision was performed and muscle samples were obtained. Samples were placed in embedding compound and immediately frozen in isopentane precooled to its freezing point. All samples were kept at 80°C until the day of analysis. The pretraining and posttraining muscle biopsy samples were obtained 10-cm apart from each other. Skeletal Muscle Analysis Fiber Typing, CSA, and Capillarization: All muscle specimens were coded and analyzed without knowledge of the clinical data. Samples obtained before and after the training period were analyzed in pairs at the same time. Cryostat transverse sections of 10 m in thickness were cut at 20°C and were stained for myofibrillar adenosine triphosphatase after preincubation at pH values of 4.3, 4.6, and 10.3. 23–24 A mean of 331 14 muscle fibers were analyzed from each slice and classified as type I, IIa, or IIb. The CSA of a minimum of 200 fibers was measured in each slice with an image analysis system (ImagePro; Media Cybernetics; Silver Spring, MD) at a known and calibrated magnification. A-amylase-periodic acid shift was used to visualize capillaries. The number of capillaries identified in a certain area was divided by the number of fibers found in the corresponding muscle section. 25 Enzyme Activity: The activities of phosphofructokinase (PFK) [enzyme code 2.7.1.11] and citrate synthase (CS) [enzyme code 4.1.3.7] were studied using described spectrophotometric techniques. 26 Assessment of Exercise Capacity Before and after the training program, an incremental protocol was performed on an electromagnetically braked cycle ergometer (Ergoline 800; SensorMedics; Yorba Linda, CA). After 3-min of baseline measurements, followed by 3-min of unloaded pedaling, the work rate was increased every min by 5 or 10 W to the limit of tolerance while patients maintained a pedaling frequency of 60 revolutions/min. Gas exchange and ventilatory variables were recorded breath-by-breath (V˙ max 229; SensorMedics). At baseline, during unloaded cycling and incremental exercise, patients performed inspiratory capacity (IC) maneuvers at 3-min intervals according to previously described methods. 27 The V-slope technique was used to detect the oxygen uptake (V˙ o 2) at which the lactate threshold (LT) occurred. 28 The modified Borg Scale 29 was used to rate the magnitude of dyspnea and leg discomfort. Statistical Analysis Data are presented as mean SEM. The within-group and between-group differences were analyzed using repeated-measures analysis of variance. Between-group comparisons of baseline characteristics were carried out by unpaired t test. The level of significance was set at p 0.05. Results Patient Characteristics As shown in Table 1, patients in both groups were characterized by severe airflow limitation, moderate hypoxemia without carbon dioxide retention at rest, and reduced values for Dlco and IC. At the outset of the study pulmonary function, exercise capacity and morphologic characteristics of the vastus lateralis muscle were not significantly different between the two groups, whereas exercise capacity was severely compromised in both groups (Tables 1–3). Training Program The average training intensity sustained at 100% and 60% of baseline Wpeak during IE and CLE training was achieved at the fifth and fourth sessions, respectively. The mean intensity sustained during training increased progressively in the IE group and corresponded to 105 13%, 130 13%, and 138 16% of baseline Wpeak and to 66 3%, Table 2—Vastus Lateralis Muscle Characteristics of Patients Assigned to the IE and CLE Training Groups at the Outset of the Study* Characteristics IE (n 10) CLE (n 9) Fiber-type distribution, % Type I 36 5 40 5 Type IIa 50 6 46 6 Type IIb CSA, m 13 2 13 3 2 Type I 3,972 455 4,634 262 Type IIa 3,695 372 3,795 231 Type IIb 3,027 407 3,127 218 Capillary-to-fiber ratio 1.13 0.08 1.30 0.09 Capillary density, capillaries/mm 2 266 18 268 12 CS activity, mol/min/g 14.3 1.4 21.6 2.6† PFK activity, mol/min/g 61.3 22.2 63.8 11.7 *Data are presented as mean SEM. †p 0.05 3840 Clinical Investigations Downloaded From: http://jupcvss.chestpubs.org/ on 08/01/2013
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