Discussion
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 H-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, muscle quality has received less attention. In a recent study, Shields et al. 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 ([almost equal to]20%), significantly larger differences are observed in intramuscular lipid infiltration ([almost equal to]75%), muscle strength ([almost equal to]50%), and walking ability ([almost equal to]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 T2 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. Elevated toxic lipid metabolites and adipose-derived cytokines impair muscle cell signaling and function, which contribute to the loss of force-producing capabilities.
Moreover, the presence of adipose cells within and between muscle fibers may interfere with muscle activation and/or disrupt force transmission 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 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.
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. 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. 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. 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).H-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.. It has been used to quantify intramuscular fat in studies of advancing age, muscular dystrophy, and spinal cord injury. This fat depot includes most of the intramyocellular triglycerides and extramyocellular adipocytes present between muscle fascicles. H-MRS and T2 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. 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; 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, 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 H-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); 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.