Peripheral muscle weakness, particularly of lower limbs, is an important complication of chronic obstructive pulmonary disease (COPD) (19). It is associated with exercises intolerance (13,32), increased health care services use (5), and increased risk of mortality (33). Although decline in strength is commonly attributable to a decrease in muscle size and cross-sectional area, atrophy alone does not fully explain the extent of muscle weakness observed in people with COPD (15,33). In addition to size, changes in muscle composition may play a role in explaining peripheral muscle weakness.
Excessive lipid deposition within the skeletal muscles are usually seen in association with atrophy in aging (23), inactivity (20), and chronic disease conditions such as diabetes (14), muscular dystrophy (35), spinal cord injury (12), and stroke (26). Increased intramuscular fatty infiltration is now identified as a contributor to declining strength and mobility, independent of muscle size (11,21,37). The potential importance of fatty atrophy in age and diseased muscles has also stimulated the application of various imaging approaches such as magnetic resonance imaging (MRI) to assess lipid content within the muscle.
In a previous study by our group (22), a standard MRI technique (T1-weighted imaging) revealed an unusual pattern of fat infiltration across three major thigh muscle groups in people with COPD. Such technique provides excellent spatial resolution to detect anatomical structures. However, quantification of fat is limited because each voxel comprising the image can contain different tissues (e.g., water, fat, connective tissue) and therefore possess a signal average of all elements (28). Proton magnetic resonance spectroscopy (1H-MRS) is used in conjunction with MRI to quantify lipid fraction within the muscle (28). 1H-MRS produces a chemical spectrum of the tissue where the areas of the spectral peaks correlate with the concentration of chemical present measured in parts per million (Fig. 1A and B). It can also be used to measure biophysical properties of the tissue (Fig. 1C and D), the transverse relaxation time (T 2). Changes in T 2 values are associated with increased water content in muscle due to inflammation and/or edema, reflecting a pathological process (16). To our knowledge, no studies have used a combination of MRI and 1H-MRS to assess muscle quality in COPD.
The recent focus on the clinical implications of intramuscular fat infiltration in chronic diseases is important because it may further explain the degree of strength deficits and mobility limitations seen in COPD. It could also potentially provide insight into the design of exercise protocols to alleviate muscle dysfunction in these individuals. Therefore, we aimed to quantify lipid and water contents (muscle quality) of lower limb muscles in people with COPD using MRI and 1H-MRS and compare them with matched control subjects. We also examined the relationship between muscle quality and muscle strength and mobility in the COPD group.
We conducted a cross-sectional study to measure muscle quality in people with moderate to severe COPD (24) age 60 yr and older before commencing pulmonary rehabilitation. Exclusion criteria comprised cardiovascular disease or uncontrolled hypertension (≥160/90 mm Hg); conditions known to affect muscle function such as oxygen therapy or oral corticosteroid use (in the past 6 months); and musculoskeletal (e.g., knee or hip arthritis), metabolic (e.g., diabetes), or neurological disorders (e.g., stroke and Parkinson’s disease). Older adults from the community were matched to COPD participants for age, gender, and body mass index (BMI) and excluded if presenting with known respiratory, cardiovascular, neurological, or musculoskeletal conditions, smoking history of greater than 10 pack-years, or were considered “active,” defined as participating in a regular aerobic or strength exercise program at least two times per week for at least 1 month. The presence of inclusion and exclusion of study participants was based on the review of the electronic patient charts for people with COPD and for healthy controls from a self-reported screening questionnaire and interview. All potential subjects were screened and consented for MRI compatibility before enrollment. We also excluded individuals who had experienced a respiratory tract infection in the past 4 wk. The hospital’s research ethics board approved the study, and participants underwent testing protocols after providing written informed consent.
Testing and procedures
Participants attended three assessment sessions. On the initial visit, we recorded demographics, anthropometry, and clinical and smoking history. Each participant also completed the self-administered Physical Activity Scale for the Elderly (38) and performed spirometry (2) and 6-min walk test (1). On the second visit, participants performed strength testing of the dominant lower limb to obtain isokinetic and isometric peak torques of knee extensors (KE) and knee flexors (KF), and plantar flexor (PF) and dorsiflexors (DF).
Muscle strength testing was done using a computerized dynamometer (Biodex System 4 Pro, Shirley, NY). Subject positioning, verbal instructions, and visual feedback were standardized. Participants performed two to three warm-up contractions at approximately 50%–75% of perceived maximum effort, followed by five maximal voluntary contractions interspersed with 60-s rests. Isokinetic contractions of KE and KF were tested at 60°·s−1 and isometric contractions at 60° of knee flexion (22). Isokinetic contractions of PF and DF were tested at an angular velocity of 30°·s−1 within the full available range of motion. Isometric contractions of DF were assessed with the ankle at 30° of plantar flexion, whereas those of PF were tested at 0° (neutral) ankle angle (39). Participants were allowed a 5-min rest between isometric and isokinetic testing and between assessments of the two joints. The highest torque achieved among the five trials for each test was used as a measure of muscle strength.
At least 3 d later, participants underwent MRI and 1H-MRS (1.5-T whole-body scanner, Signa; GE Medical Systemsb, General Electric, Milwaukee, WI) of the same limb. In a supine position, the subject’s lower limb was positioned in an eight-channel phased array knee coil for lower leg imaging and a cardiac coil for thigh imaging. The limb was centred in the coil to ensure that the CSAmax of the muscles of interest had adequate coverage. Transaxial images were acquired using a spoiled gradient echo sequence with the following parameters: TR = 5.7 ms, TE = 2.7 ms, acquisition matrix of 256 × 256 pixels, slice thickness of 7 mm and slice gap of 7 mm, flip angle = 10°, and optimized field of view (calf ∼25 cm2, thigh ∼40 cm2). 1H-MRS was used to quantify intramuscular lipid and T 2 of the vastus lateralis (VL) and soleus (SO) muscles. T 2 relaxation time of only the soleus muscle was quantified. Volume localised unsuppressed spectra from the VL and SO muscles were acquired using a stimulated echo technique (STEAM). The transaxial images were used to guide placement of a large voxel (∼35 mm3, i.e., five slices) inside the muscle belly parenchyma of the VL and SO muscles near the CSAmax, avoiding visible vasculature, subcutaneous fat, and myofascial layers. To measure muscle lipids, 32 signal averages were acquired with a TE of 120 ms and TR of 6000 ms (2500 Hz spectral width, 512 points). T 2 relaxation time of the soleus muscle was determined from acquiring spectra at five echo times (TE array = 13, 27, 45, 108, and 120 ms; number of excitations = 4). Automated optimization of gradient shimming was used to optimize line widths.
Maximal muscle cross-sectional area
Muscles cross-sectional areas (CSA) were manually outlined on each of 20 transaxial slices of the thigh and calf using open source software (OsiriX, http://www.osirix-viewer.com/). Tracings of individual muscles from each of the transaxial slices were summed to obtain a cumulative CSA of the quadriceps (rectus femoris and vasti), hamstrings (semitendinosus, semimembranosus, and biceps femoris), triceps surae (soleus, medial, and lateral gastrocnemius), and DF (tibialis anterior). The axial image with the largest CSA in the series was identified and averaged with the CSA in the immediate proximal and distal slices to obtain the CSAmax of the muscle group.
Muscle lipid and water contents
Concentrations of lipid and water within the muscle were determined using commercially available software (jMRUI). After a zero-order phase correction, water and lipid concentrations were quantified via peak detection (AMARES algorithm). To assess the lipids, we included all lipid peaks from 0.5 to 2.75 ppm, and the water peak included values between 4.30 and 5.10 ppm (Fig. 1A and B). Concentrations of lipid were determined relative to water, and fraction ratio (lipid/total proton) was calculated and considered as a measure of lipid infiltration. To calculate soleus T 2 relaxation time, the spectral peak for water at 4.7 ppm was determined at each TE (13, 27, 54, 108, and 120 ms). Curve fitting was used to calculate T 2 (in milliseconds) from the following equation: signal intensity = ke(1/T 2 x) + c, where k = 6 × 108 (Fig. 1C and D).
Sample size and power
We used the G*power analysis program to calculate the study sample size considering the lipid/total proton ratio as the primary outcome. Using data from spinal cord injury study (29), we estimated seven participants in each group to detect differences in muscle lipid content (effect size, ∼1.77 and ∼2.01) with a statistical power of 0.90 and α = 0.05. Assuming that less intramuscular fat would be present in COPD, a final sample of 10 participants was targeted.
Results are reported as mean (SD) and percentage difference, unless stated otherwise. Between-group differences and correlations between study variables were tested using a two-tailed independent sample t-test and a Pearson product–moment correlation coefficient, respectively (or nonparametric equivalents). We used STATA11 statistical package (StataCorp LP, College Station, TX) and an alpha level of 0.05 for all tests.
Study participants were matched for sex, age, and BMI (Table 1). People with COPD had lower mean 6-min walk distance percent of predicted (6MWD%pred) than healthy individuals (49% ± 26% vs 99% ± 14%, respectively; P < 0.001) for similar self-reported physical activity levels as the control group (83 ± 53 vs 106 ± 56; P = 0.37).
Participants with COPD exhibited significantly lower absolute peak torques than controls for KE and PF (Table 2). Absolute values for KF and DF were not significantly different between COPD and control groups either for isokinetic (58 (18) vs 69 (31) N·m and 26 (17) vs 27 (12) N·m, respectively) or for isometric peak torques (63 (24) vs 80 (49) N·m and 32 (10) vs 34 (18), respectively). Peak torque normalized to the CSAmax was similar between groups for all muscle groups, except for PF (P = 0.002). The percentage mean difference between groups in isokinetic peak torques was significant for KE (46%, P = 0.024) and PF (35%, P = 0.04) but not for KF (18%, P = 0.113) and DF (4%, P = 0.227). For isometric peak torques, the between-group differences were also significant for KE (35%, P = 0.041) and PF (52%, P = 0.002) but not for KF (24%, P = 0.091) and DF (7%, P = 0.907).
Muscle size and quality
People with COPD illustrated significantly smaller muscle size and presented greater lipid infiltration than controls for KE and PF (Table 2). Absolute values for KF and DF were not significantly different between COPD and control groups (34.5 (8) vs 39 (6) cm2 and 12.5 (2) vs 15 (4), respectively). The percentage of the mean difference between groups in CSAmax was significant for KE (20%, P = 0.031) and PF (25%, P = 0.024) but not for KF (11%, P = 0.510) or DF (24%, P = 0.061). COPD patients had significantly higher lipid/total proton ratios when compared with control subjects. The percentage of mean difference between the two groups in intramuscular lipid infiltration was 74% (P = 0.005) in VL and 89% (P = 0.001) in the soleus. Soleus T 2 relaxation time was similar between the COPD and control groups (34.4 ± 3.3 and 32.9 ± 1.8, respectively; P = 0.21).
Muscle function and mobility
Moderate correlations were found between CSAmax and isometric and isokinetic peak torques in the COPD group (KE muscles: r = 0.427, r = 0.567 (P < 0.05); and PF muscles: r = 0.389, r = 0.432 (P < 0.05)). However, correlations between muscle size and walking distance were statistically significant only for CSAmax of PF muscles and 6MWD%pred (r = 0.699, P < 0.001). As shown in Figure 2, strong negative correlations were found in people with COPD between lipid/total proton ratios and isometric and isokinetic peak torques of KE and PF muscles as well as 6MWD%pred (r = −0.7 to −0.8, P < 0.001). Likewise, the lipid/total proton ratio was correlated with KE and PF peak torques (r = −0.4, P < 0.01) as well as 6MWD%pred (r = −0.3, P < 0.04) in the healthy subjects, but neither KE CSA nor PF CSA showed significant correlation (P < 0.172) with the distance walked in this group.
This study provides novel evidence of intramuscular fat infiltration in COPD and its relationship with impaired muscle strength and mobility. We are the first to use MRI and 1H-MRS to quantify muscle quality in this population. Our findings demonstrate that, in addition to muscle atrophy, there is a lipid accumulation in lower limb muscles of people with COPD that is significantly greater than what is observed in their healthy counterparts. Moreover, increased intramuscular fat infiltration has a stronger correlation with muscle weakness and impaired mobility than muscle size in this group.
Whereas declines in both muscle mass and muscle strength of lower limbs are well documented in COPD (19), muscle quality has received less attention. In a recent study, Shields et al. (30) used an image-based technique (Dixon method) to quantify the amount of fat within the fascial envelope of quadriceps muscles, termed intermuscular adipose tissue, in people with COPD. The authors reported an increase in intermuscular adipose tissue in COPD compared with healthy controls that was associated with abnormal muscle metabolism during exercise in this group. Our study provides additional novel data on the presence of ectopic fat within the muscle (intramuscular) and its relationship with health-related outcomes in COPD. In fact, although our COPD participants have smaller muscle size (≈20%), significantly larger differences are observed in intramuscular lipid infiltration (≈75%), muscle strength (≈50%), and walking ability (≈60%) between the two groups. In addition, stronger correlations exist between strength and walking distance with intramuscular fat infiltration than with muscle size in the COPD group. No increase in muscle T 2 in the soleus muscle between groups provide further evidence that muscle composition in COPD is primarily affected by lipid infiltration rather than edema. Lastly, comparisons between our COPD participants and matched healthy controls subjects might suggest that disease-specific factors may account for intramuscular fat infiltration in these individuals.
The presence of adipose tissue within skeletal muscle in addition to the increase in lipid content could play a crucial pathogenetic role and represents a negative prognostic factor for several myopathies, metabolic diseases, and aging. The cellular and molecular pathways of intramuscular fat infiltration and the mechanisms by which it affects skeletal muscle function are still unclear. High levels of plasmatic fatty acids (oversupply), imbalance between fatty acid uptake, and oxidation and myocell adipogenic differentiation cells differentiating into adipogenic cells have been considered potential mechanisms responsible for lipid accumulation in the muscle (34,36). Elevated toxic lipid metabolites and adipose-derived cytokines impair muscle cell signaling and function, which contribute to the loss of force-producing capabilities (3,6,41).
Moreover, the presence of adipose cells within and between muscle fibers may interfere with muscle activation (40) and/or disrupt force transmission (8) leading to contractile dysfunction. The close anatomical proximity between fat and muscle cells implies a reciprocal influence, and muscle cytokines and metabolites could then affect the surrounding adipose tissue function. Physiological conditions such as physical exercise and pharmacological treatment (4) could influence the rate of satellite cell-derived myofibers entering the adipogenic lineage and modifying the adipokine expression profile and pattern of fat cells within the muscle bundles (36).
Despite the underlying mechanisms, extra- and intramyocellular lipid deposition is inversely associated with muscle strength and mobility in healthy individuals as well as those with pathological conditions (14,21,27). Our results corroborate the literature findings in healthy older adults. Little is known about change in muscle quality and its effect on physical functioning in people with COPD. Roig et al. (25) have reported muscle attenuation characteristics in the thigh of 21 people with COPD using computed tomography. Although the COPD group showed twice the numbers of pixels within the range of lipid attenuation (Hounsfield units) as matched control subjects, nonsignificant associations were found between the quality of the muscles and measures of mobility, including 6MWD. In a recent study, Maddock et al. (18) assessed thigh muscle quality in 101 people with COPD and demonstrated a strong association between lipid attenuation (in Hounsfield units) and percentage of intramuscular fat (normalized to midthigh cross-sectional area) with incremental shuttle and 6-min walk tests as well as step count. However, neither measures of muscle adiposity were significantly associated with quadriceps strength.
Our study illustrates a strong correlation between increased intramuscular lipid ratios and isometric and isokinetic muscle strength as well as walking distances in the COPD group. Differences in findings between both investigations and our study are likely to be attributable to accuracy of the methods used in quantitative assessment of muscle composition. Computed tomography imaging, such as that employed in the previous studies, provides a relatively crude determination of the lipid content because other factors can still contribute to altered muscle attenuation (e.g., alteration in muscle protein or water content) (10). 1H-MRS has long been considered the gold standard for noninvasive quantification of ectopic fat, and its use in skeletal muscles was first described by Schick et al. (28). It has been used to quantify intramuscular fat in studies of advancing age (23), muscular dystrophy (35), and spinal cord injury (29). This fat depot includes most of the intramyocellular triglycerides and extramyocellular adipocytes present between muscle fascicles. 1H-MRS and T 2 quantification, as employed in our investigation, are highly reproducible and sensitive methods for determination of muscle composition providing specific measures of muscle lipid and water contents, respectively.
Another novel finding in this study concerns the poor quality and function of calf muscles in people with COPD. Unlike quadriceps, less is known about structure and function of these muscles that are also important contributors to walking and balance. In a recent study, PF muscle weakness and fatigability after walking exercise is reported to be greater in people with COPD compared with healthy controls (7). To our knowledge, we are the first to show that weakness of the calf muscle is also accompanied by increased fat infiltration, independently of muscle atrophy. Moreover, we found similar relationships between fat infiltration of the soleus with 6MWD, punctuating the importance of the PF muscles in functional limitations in COPD.
Results of the present study extend our understanding of the underlying limb muscle dysfunction in COPD. MRI and spectroscopy findings confirm increased fat infiltration in thigh and calf muscles of people with COPD compared with healthy counterparts and underscore that poor muscle quality may account for individual’s impaired function. Longitudinal investigations and analysis of larger COPD cohorts could further the generalizability of our findings and verify the causal mechanisms linking lipid accumulation to impaired strength and mobility.
Limb muscle dysfunction and physical inactivity are observed even in individuals with mild COPD (31); therefore, investigations to examine whether changes in muscle quality occur at early stages of the disease and in smokers with normal lung function are also warranted. The association between muscle quality and the resultant inactivity in COPD also needs further studies using more direct measurements of the amount and intensity of daily physical activity (e.g., accelerometry). Because intramuscular fat infiltration might be modifiable (9,27), an improved characterization of changes in muscle composition may enable specific types of exercise training to be developed to address them, thereby optimizing outcomes from pulmonary rehabilitation. Well-controlled randomized studies are needed to examine the potential for exercise to reduce fat infiltration and improve muscle quality in addition to size and strength in COPD.
The relatively small separation of fat and water proton spectral peaks of 1H-MRS at 1.5 T in this study does not allow us to differentiate intramyocellular or extramyocellular lipid compartments of the spectrum. This may be more feasible at higher field strengths (3 T or higher), where peak separation increases. Intramyocellular lipid is frequently associated with metabolic dysregulation (e.g., insulin resistance and type 2 diabetes) (17); therefore, the differentiation of lipid compartments may be an important factor in the quantitative evaluation of muscle quality in future studies. The relationship between fat deposition within skeletal muscle on the metabolic profile of people with COPD also represents a future area for research.
Intramuscular fat infiltration is significantly increased across thigh and calf muscles in people with severe COPD when compared with matched healthy older adults. Poor muscle quality is more profound than muscle atrophy and better correlated with muscle weakness and impaired mobility in this group. MRI and 1H-MRS offer a noninvasive quantitative method to detect skeletal muscle changes in COPD. Monitoring changes in both muscle size and quality may enable a more comprehensive assessment of exercise training programs in improving physical functioning in COPD.
The authors thank Neil Spiller and Eugen Hlsany from the Joint Department of Medical Imaging, Toronto General Hospital—University Health Network, as well as Meeran Manji from the Pulmonary Rehabilitation Clinic, Toronto Western General Hospital—University Health Network. Preliminary findings were presented at the American College of Sports Medicine and Canadian Society for Exercise Physiology conferences. Ontario Respiratory Care Society and Dean’s Start-up Fund, University of Toronto, supported this work.
The authors have no conflict of interest to disclose. The results of the present study do not constitute endorsement by the American College of Sports Medicine.
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