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Purpose: Exercise limitation in recipients of lung transplant may be a result of abnormalities in the skeletal muscle. However, it is not clear whether these abnormalities are merely a reflection of the changes observed in the pretransplant condition. The purpose of this paper was to compare thigh muscle volume and composition, strength, and endurance in lung transplant recipients to people with chronic obstructive pulmonary disease (COPD).
Methods: Single lung transplant recipients (n=6) and people with COPD (n=6), matched for age, sex, and BMI participated in the study. Subjects underwent MRI to determine muscle size and composition, lower extremity strength testing and an isometric endurance test of the quadriceps.
Results: Lung transplant recipients had similar muscle volumes and intramuscular fat infiltration of their thigh muscles and similar strength of the quadriceps and hamstrings to people with COPD who had not undergone transplant. However, quadriceps endurance tended to be lower in transplant recipients compared to people with COPD (15 ± 7 seconds in transplant versus 31 ± 12 seconds in COPD, p = 0.08).
Conclusions: Recipients of lung transplant showed similar changes in muscle size and strength as people with COPD, however muscle endurance tended to be lower in people with lung transplants. Impairments in muscle endurance may reflect the effects of immunosuppressant medications on skeletal muscle in people with lung transplant.
Lung transplantation is a highly beneficial treatment resulting in improved survival rates and quality of life in people with end-stage, chronic respiratory diseases such as chronic obstructive pulmonary disease (COPD), cystic fibrosis, and restrictive lung diseases.1 Although pulmonary function improves following lung transplantation, recipients of lung transplants still experience limited exercise capacity (40% to 60% of predicted) even up to 1 year following the transplant.2,3 Exercise limitation has been attributed to factors related to oxygen delivery and utilization by skeletal muscle4,5 and changes in the metabolic properties of skeletal muscle in lung transplant recipients.5,6 Reinsma et al7 examined factors limiting exercise capacity in people with varying pretransplant diagnoses, both before and 1 year following transplant and suggested that peripheral muscle dysfunction was the major contributor to limited exercise capacity post-transplant. Skeletal muscle abnormalities in transplant recipients have been attributed to a prolonged period of bedrest and low activity levels pre- and post-transplant and the use of immunosuppressant medications such as calcineurin inhibitors and corticosteroids.1,7
Skeletal muscle abnormalities beyond the metabolic characteristics of muscle have not been studied extensively in recipients of lung transplants. Muscle mass, strength, and endurance are important characteristics of skeletal muscle that may also be affected by inactivity and the secondary effects of medications. Furthermore, the pretransplant condition (ie, COPD) is associated with reduced muscle mass8 and muscle fiber atrophy,9 muscle weakness,10 and reduced muscle endurance11 compared to healthy people of the same age. Following lung transplantation, these characteristics of skeletal muscle may be further impaired.
The majority of studies examining exercise capacity and/or skeletal muscle characteristics in people with lung transplant either do not include a control group12,13 or compare them to a healthy control group.4–6,14,15 However, to determine whether the changes observed in skeletal muscle are due to the pretransplant condition or to factors related to post-transplant care, comparisons need to be made to people who have a chronic respiratory condition. Since COPD is known to be associated with skeletal muscle abnormalities and is also a major indication for lung transplantation,16 it provides an excellent model for comparison to determine whether skeletal muscle changes observed following lung transplant are merely a reflection of the pretransplant condition or whether they are worsened post-transplant.
The purpose of this paper was to compare the muscle volume, intramuscular fat infiltration, and strength of individual muscle groups of the thigh, and muscle endurance of the quadriceps in people with COPD and restrictive lung disease who were recipients of lung transplants (lung transplant group) to those who had not undergone lung transplant (COPD group). We hypothesized that lung transplant recipients would have greater impairments in skeletal muscle (ie, lower muscle volume, strength, and endurance) than the COPD group.
Recipients of single lung transplant were recruited from the Solid Organ Transplant Clinic over a 1 year period (2003-2004). Single lung transplant is the preferred procedure in people with COPD or pulmonary fibrosis at our center. Letters were sent to potential participants and 10 lung transplant recipients volunteered to participate in this study, of which 6 met the inclusion criteria (see Table Table1).1). People with COPD were recruited from patient lists at the respiratory clinic and pulmonary function labs. Specific inclusion criteria are provided in Table Table1.1. People with COPD were matched to the recipients of lung transplant based on sex, age (± 4 years), and BMI (± 2.0 kg/m2). Subjects with COPD had a stable condition and none were awaiting lung transplant.
The study was approved by the local University Clinical Research Ethics Board and all subjects provided written, informed consent. Each participant completed the Physical Activity Scale for the Elderly (PASE).17 The PASE is a 12-item, self-administered questionnaire that asks about household, leisure time, and work-related physical activity over the past 7-day period. Height and weight were measured with shoes off and light clothing.
Participants underwent spirometry according to American Thoracic Society standards18 to measure forced expiratory volume in one second (FEV1) and forced vital capacity (FVC). Values were expressed as percent of predicted.19 For lung transplant recipients, bronchiolitis obliterans syndrome (BOS) stage was calculated by comparing the average of 2 measurements of FEV1 made at least 3 weeks apart to the subject's previously established baseline FEV1.20 Any decline in FEV1 was staged according to published guidelines.20
An incremental exercise test was conducted on an electrically-braked cycle ergometer. Workload was increased by 10 Watts per minute until symptom-limited maximum was achieved. Participants were connected to a metabolic cart (VMax 229, Sensormedics, Yorba Linda, Calif) which consisted of a pneumotachograph, O2 and CO2 analysers, and a mixing chamber. Breath-by-breath analysis was used to obtain minute ventilation (VE), oxygen uptake (VO2), and carbon dioxide production (VCO2). Heart rate was monitored using 12-lead ECG (Quinton Eclipse Premier, Bothell, Wash) and oxygen saturation (% SpO2) was monitored using a finger pulse oximeter (SiMed S103, Miami, Fla). Blood pressure was measured manually at rest and one minute intervals throughout the test. Participants were asked to rate shortness of breath and leg fatigue separately throughout the test using the Rating of Perceived Exertion (RPE) category-ratio scale.21 Peak VO2 and workrate were expressed as a percent of predicted.22
An MRI was used to estimate quadriceps, hamstrings, and adductor muscle volume as previously described.23 Briefly, a 1.5 Tesla MRI scanner (1.5T Echospeed Scanner, General Electric, Milwaukee, Wis) was used to acquire 5-mm axial contiguous slices from the femoral-tibial joint line to the anterior superior iliac spine on both thighs. Images were T1-weighted (TE = 8 ms; TR = 650 ms) with a 40cm2 field of view and a 512 × 224 pixel matrix (in-plane spatial resolution = 0.78 × 1.78 mm).
NIH Image, version 1.3.1 (http://rsb.info.nih.gov/ij/Java1.3.1._03) was used to manually outline the quadriceps [rectus femoris (RF), the vasti (vastus lateralis, vastus intermedius, and vastus medialis)], hamstrings (semitendinosis, semimembranosis, biceps femoris long head and short head) and the adductors (adductors longus, brevis, and magnus). Muscles were outlined on 17 slices, with a gap of 2.0 to 2.5 cm between measured slices. The first slice was chosen at the origin of the RF muscle (approximately 2 cm below the anterior inferior iliac spine) and the last slice was at the superior aspect of the patella. The distance between the first and last slices was divided equally into 16 slices. The total volume of the muscle was calculated by summing the product of measured muscle cross-sectional areas by the slice thickness of all 17 sections, and the volume of the gaps between slices was estimated using the truncated cone formula as previously described.24 Individual muscles are shown in Figure Figure1A1A and Figure Figure1B1B.
To determine the degree of intramuscular fat infiltration, the RF, vasti, semitendinosis, and biceps femoris (long head) were outlined on the mid-thigh slice and NIH Image was used to generate a frequency distribution of signal intensity for each muscle (Figure (Figure1C).1C). The interquartile range (IQR), ie, the number of pixels in the 25th to 75th percentile of signal intensity, was calculated for each distribution and a greater IQR was indicative more fat infiltration.25 Secondly, a coefficient of skewness was calculated to describe the asymmetry of the frequency distribution. A normal distribution is symmetric, and has a skewness value of zero whereas a distribution with a significant positive skewness has a long right tail indicative of pixels with higher signal intensity, ie, greater fat.25
Concentric and eccentric torque of the KEs and KFs were performed on the KinCom dynamometer (version 5.30, Chattanooga Group Inc, Hixson, Tenn) which is a valid and reliable instrument for measuring torque.26,27 Each participant was seated on the dynamometer with straps placed across the hips and shoulders, and the knee joint carefully aligned with the axis of rotation of the dynamometer. The shin pad was placed at 75% of the distance from the head of the fibula to the distal edge of the lateral malleolus. Each participant performed 5 submaximal warm-up contractions followed by 3 to 4 maximal voluntary concentric and eccentric contractions at 30°/s through a range of motion from 100° of flexion to full available extension. Peak torques of the KEs and KFs were normalized to muscle volume of the quadriceps and hamstrings, respectively and expressed in Nm/cm3.
Each participant performed a KE muscle endurance task consisting of an isometric contraction held at 80% of their maximal voluntary isometric contraction (MVIC) on the KinCom dynamometer. The knee joint was placed at 90° of flexion for testing. The MVIC was determined from 3 MVICs of the KEs with a 1 minute break given between trials. The participant was instructed to "push as hard as possible" over a 5-second period. The highest value was used to calculate the target torque for the endurance task (80% MVIC).
Following a 5-minute rest the endurance task was performed. During the endurance task the subject was asked to maintain their target torque for as long as possible. Visual feedback of the target and produced torque was provided and verbal encouragement was given by the tester to maintain the force at the target level until the target torque could no longer be met despite verbal cueing. The time to task failure was defined as the point where the produced torque dropped 20% from the target level and was calculated from the software program. The participant was asked to rate their leg fatigue at the end of the contraction using the RPE scale.
Descriptive statistics (mean and standard deviation) were used to describe subject characteristics, muscle volume, torque, and endurance time. The mean difference and 95% confidence interval (95% CI) for the difference between the groups was calculated from one-way ANOVA, and the level of significance was set at α = 0.05. The 95% CI is helpful in determining whether a clinical meaningful difference exists, especially when comparing small samples of subjects. Post-hoc power analysis was completed using statistical software package, G-Power (version 3).28 Effect size was calculated as the difference between the group means divided by the average of the standard deviations observed from each group for the measure of interest [(mean1 – mean2)/SD].
Recipients of lung transplant and people with COPD were closely matched for sex, age, height, weight, and BMI (Table (Table2).2). As shown in Table Table3,3, all recipients of lung transplant were receiving a regimen of immunosuppressant medications consisting of a calcineurin inhibitor (cyclosporine or tacrolimus), a purine synthesis inhibitor (azathioprine or mycophenalate mofetil), and a corticosteroid (ie, prednisone). Recipients of lung transplant were not showing significant chronic allograft dysfunction (BOS scores 0-1).
Recipients of lung transplant all received single lung transplants and their lung function was lower than predicted values (FEV1 = 63% ± 9% of predicted and FVC = 68 ± 10% of predicted), however, were higher than in people with COPD (p < 0.01) (see Table Table2).2). Peak VO2 was limited in both groups compared to predicted values: 59% and 53% of predicted in transplant recipients and people with COPD, respectively. All subjects reported leg fatigue to be greater than shortness of breath at the end of exercise using the RPE scale.
Each subject's quadriceps, hamstrings, and adductor muscle volumes are shown Figure Figure2.2. Muscle volume tended to be lower in the transplant recipients compared to people with COPD by 6.5% for the quadriceps (mean difference = −83.6, 95% CI = −594.2 to 426.6 cm3), 2.3% for the hamstrings (mean difference = −11.6, 95% CI = −189.6 to 166.3 cm3), and 13.8% for the adductors (mean difference = −87.9, 95% CI = −375.2 to 199.4 cm3); however, no significant difference was observed between groups (p = 0.71 to 0.98).
Interquartile range and coefficients of skewness were used to quantify the degree of intramuscular fat infiltration in individual muscles on the thigh (Table (Table4).4). Lung transplant recipients and people with COPD showed the presence of intramuscular fat, as shown by coefficients of skewness greater than one; however there was no significant difference observed between the groups (p = 0.14 to 0.99).
Knee extensors and knee flexors absolute torques are shown in Figure Figure3.3. The largest mean difference between groups was seen for the KE eccentric torque (15 Nm, 95% CI = −56 to 26 Nm), however other mean differences were small, ranging from no difference (ie, 0) to 6 Nm. The KE and KF torques were then normalized for quadriceps and hamstrings muscle volumes, respectively, to account for differences in muscle volume between subjects (Figure (Figure4).4). Mean differences between groups for normalized torque were small, ranging from 0.0003 to 0.008.
Endurance times for individual recipients of lung transplant and people with COPD are shown in Figure Figure5.5. Although initial isometric torque was similar between groups (75 ± 27 N/m in transplant compared to 71 ± 18 N/m in COPD), mean isometric endurance time had a tendency to be lower in transplant recipients compared to COPD (mean difference of −13 seconds, 95% CI= −29 to 2, p=0.08). Rating of perceived exertion for leg fatigue at the end of the endurance task was also similar between groups (6 ± 1 and 7 ± 1 in transplant and COPD, respectively).
The main findings of this study demonstrate that recipients of lung transplant have similar muscle volumes of the thigh, a similar degree of intramuscular fat infiltration, and similar strength of the KEs and KFs compared to people with pre-existing chronic respiratory disease, mainly COPD. However, isometric endurance of the quadriceps muscle tended to be lower in recipients of lung transplant compared to people with COPD. Our study is unique since it compared a group of people with lung transplant to people with COPD who were matched for sex, age, and BMI. This allowed us to draw comparisons between pre-existing muscle dysfunction associated with COPD to that which occurs following lung transplant. Our findings indicate that muscle mass, composition, and strength are likely affected to a similar degree in recipients of lung transplant as compared to people with COPD, whereas muscle endurance may show a tendency to be lower in transplant recipients.
This study is the first to quantify muscle volume of 3 muscle groups of the thigh in people with lung transplants using specific measurements from MRI. We found that volumes of the quadriceps, hamstrings, and adductors in people with lung transplants were similar to those seen in the COPD group, although there was a tendency for the transplant group to have a lower mean volume than people with COPD. A post-hoc power analysis indicated that a sample of at least 50 subjects per group would be required to determine whether recipients of lung transplant actually show a lower muscle volume than people with COPD. A previous study showed that quadriceps cross-sectional area was 31% lower in recipients of lung transplants who had cystic fibrosis compared to age-matched controls15 whereas patients with COPD have been reported to have a mid-thigh cross-sectional area which is 24% of controls.8
People with lung transplant also showed a similar degree of intramuscular fat infiltration compared to people with COPD. We have previously showed that people with COPD have higher fat infiltration in their thigh muscles compared to age, sex, and BMI-matched controls.25 The presence of fat infiltration in recipients of lung transplant may be associated with muscle atrophy as has been reported in older individuals or as a result of steroid-induced muscle myopathy.29 Fat infiltration may contribute to poor muscle function (ie, strength)30 and also to metabolic complications.31
Although pulmonary function is improved following single lung transplantation, factors that affect muscle mass and muscle quality in people with chronic lung disease, pretransplant, such as inactivity, corticosteroid medications, nutritional factors, oxidative stress, and systemic inflammation32 are likely to play a persistent role in muscle atrophy following transplant. Rehabilitative strategies that are used in people with COPD to improve muscle mass and strength such as resistance training33 as well as nutritional34 and hormonal supplementation,35 may also be beneficial in the rehabilitation of people with lung transplant and require further investigation in this population.
Peripheral muscle force has been reported to be lower in recipients of lung transplant compared to a matched control group14 and also compared to predicted values.7,13 Furthermore, Reinsma et al7 showed that one year following lung transplantation, isometric quadriceps muscle force still only reached 67 ± 19% of predicted, compared to 62 ± 19% in the same subjects prior to transplant. Similarly, we found that compared to people with COPD, people with lung transplant had similar concentric and eccentric torque of the KEs and KFs. As there were differences between individuals in muscle volume, we also normalized torque of the KEs and KFs to muscle volume of the quadriceps and hamstrings and found that normalized torque was also similar between groups. Since muscle mass is a major contributor to muscle strength,8 muscle atrophy likely plays an important role in the loss of muscle strength in transplant recipients and needs to be addressed through rehabilitation.
Quadriceps endurance time tended to be shorter in recipients of lung transplant compared to people with COPD. The observed effect size for this difference was 1.62 and to obtain a significant difference between groups, a sample of at least 9 subjects per group would have been needed. As the quadriceps endurance task depended primarily on anaerobic metabolism since it was a high intensity, isometric contraction (80% of MVIC),36 our findings likely reflect impairments in anaerobic metabolism, which is consistent with previous studies. For instance, Evans et al4 showed that recipients of lung transplant had a lower resting pH of the quadriceps muscles and an earlier drop in pH during bilateral knee extension exercise to exhaustion. This suggests that there is an earlier onset of glycolytic metabolism in people with lung transplant with exercise that can limit endurance. Impairments in the metabolic properties of skeletal muscle of recipients of lung transplant may be due to the secondary effects of immunosuppressant medications that affect calcium handling. Calcium uptake and release by the sarcoplasmic reticulum and potassium homeostasis across the sarcolemma are important aspects of skeletal muscle contractility and are linked to muscle fatigue in humans.37 Abnormalities in skeletal muscle calcium and potassium regulation have been observed in lung transplant recipients and may result in impairments in excitation-contraction coupling and contribute to the early onset of muscle fatigue.37
Our study reports preliminary findings in a small sample of people following lung transplant, compared to people with chronic lung diseases, mainly COPD. Although our study lacked adequate power to determine statistical significance, this comparison provides insight as to whether skeletal muscle dysfunction following lung transplant is merely a reflection of abnormalities observed in people with chronic lung disease or whether changes in skeletal muscle persist or are accentuated following lung transplant. Furthermore, this study included subjects with a large range of time since transplant (14 to 84 months), which likely introduced an additional source of variance to the data. To address these issues further, a larger, longitudinal study design, which follows people with chronic lung diseases both before and after transplant over a long term, needs to be conducted.
We also included 1 subject who had a pretransplant diagnosis of sarcoidosis, however, this likely did not affect our results, since skeletal muscle changes have been shown to be similar to people with COPD38 and this subject was also of a similar age to the other subjects in the COPD group.
Recipients of lung transplants show similar changes in muscle mass, intramuscular fat infiltration, and muscle strength as people with chronic lung disease. Muscle endurance, however, may show a tendency to be affected to a greater degree in recipients of lung transplants. This may be result of factors which are present post-transplant, such as the secondary effects of immunosuppressant medications on skeletal muscle. Similar rehabilitative strategies used to improve muscle mass and strength in people with COPD, such as resistance exercise training, may also be applicable to lung transplant recipients.
The authors would like to acknowledge funding for this study from the Canadian Institutes of Health Research (CIHR) and British Columbia Medical Services Foundation. The authors would also like to thank the Solid Organ Transplant Clinic at Vancouver General Hospital, the Pulmonary Function Lab at Vancouver General Hospital and the GF Strong Rehabilitation Research Lab for assistance with subject testing.