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* From the Department of Pulmonology, University Maastricht, Maastricht, The Netherlands.
Correspondence to: Emiel F.M. Wouters, MD, PhD, FCCP, Department of Pulmonology, University Maastricht, PO Box 5800, 6202 AZ Maastricht, The Netherlands; e-mail: ewo{at}slon.azm.nl
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Introduction |
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 TOP Introduction Body Composition in COPDPathogenesis of Differences in...Differences in Muscular...ConclusionReferences |
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Abbreviations: ADP = adenosine diphosphate; ATP = adenosine triphosphate; BMC = bone mineral content; BMI = body mass index; COX = cytochrome oxidase; FFM = fat free mass; GLU = glutamate; IMP = inosine monophosphate; MHC = myosin heavy chain; MLC = myosin light chain; NAD = nicotinamide adenine dinucleotide; NADH = reduced NAD; PCr = creatine phosphate; Pi = inorganic phosphate; REE = resting energy expenditure; sTNF-R = soluble TNF-receptor; TNF = tumor necrosis factor
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Body Composition in COPD |
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TOPIntroductionBody Composition in COPDPathogenesis of Differences in...Differences in Muscular...ConclusionReferences |
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The importance of measuring FFM is emphasized by the fact that depletion of FFM, indicating loss of muscle mass, contributes significantly to peripheral muscle weakness and impaired exercise capacity in COPD,5 6 7 8 as well as to health-related quality of life.9 10
Intrigued by the historically reported differences in anthropometry between the bronchitic and emphysematous patients, researchers performed studies to assess body composition in both COPD subtypes. Body composition can now easily be assessed by different noninvasive methods, and stratification of COPD patients into an emphysematous group and a group with chronic bronchitis without parenchymal involvement can be approached by high-resolution CT procedures.12 13
Engelen et al11 studied body composition in a large group of COPD patients who had been classified, on high-resolution CT criteria, as suffering from either emphysema or chronic bronchitis. Whole body FFM, consisting of lean mass and bone mineral content (BMC), was determined by scanning all patients and healthy volunteers on a DPX-L Bone Densitometer (Lunar Radation; Madison, WI). Lean mass depletion was found in 37% of the emphysema patients, in 12% of the chronic bronchitis patients, and in 4% of the healthy controls. Lean mass depletion was found in 16% of the emphysema patients and in 8% of the chronic bronchitis patients, despite normal body weights in both groups. Body weight and body mass index (BMI) were lower in the emphysema group than in the healthy controls. The lower body weights were the result of a lower lean mass index and a lower BMC index. No significant differences were found in the fat mass index between the two groups. Body weight, BMI, lean mass index, and FFM indexes were not different between the chronic bronchitis patients and the control group. The chronic bronchitis patients had lower values for BMC index and higher values for fat mass index and percentage of body fat.
Body weight and composition were significantly different between the group with chronic bronchitis and the group with emphysema. The emphysema patients had lower values for BMI, FFM index, and fat mass index than the group with chronic bronchitis. The lower FFM index was the result of a lower lean mass index and a lower BMC index. Based on these data, we can conclude that substantial differences in body composition can be found between COPD patients and healthy volunteers, as well as between chronic bronchitis patients and emphysema patients.
In a further study, the presence and contribution of FFM depletion in the extremities was studied with respect to the problem of muscle weakness in COPD. Engelen et al14 reported that whole body and extremity FFM were lower in emphysematous and chronic bronchitis patients than in controls, but that trunk FFM was lower only in emphysematous patients. Extremity FFM was comparable between the COPD subtype patients. In both COPD groups, absolute skeletal muscle function and muscle function per kilogram of whole body FFM were lower than in healthy persons. Muscle function was comparable in subjects with chronic bronchitis and in those with emphysema. Muscle function per kilogram of extremity FFM was not different between the studied groups and was not related to FEV1.
Therefore, it can be concluded that extremity FFM wasting is associated with skeletal muscle weakness independent of the COPD subtype, but that marked differences in body composition can be demonstrated between the emphysematous patient and the patient suffering from chronic bronchitis.
Although from a functional point of view, most attention in body composition assessment is focused on FFM or on muscle mass, recent data emphasize the intriguing role of fat mass in energy homeostasis. Fat mass is not just an energy reservoir; it plays an important role in energy homeostasis by producing leptin. This adipocyte-derived hormone represents the afferent hormonal signal to the brain in a feedback mechanism that regulates fat mass. Leptin also has a regulating role in lipid metabolism and glucose homeostasis, and it increases thermogenesis.15 16 Additionally, it has effects on T-cell mediated immunity.17
Few data are reported on leptin metabolism in COPD patients. Takabatake et al18 recently reported that serum leptin levels were significantly lower in COPD patients than in healthy controls. COPD patients in his study had a significantly lower BMI and percentage of body fat than the healthy control subjects. Circulating leptin correlated well with BMI and percentage of fat, as expected. Based on the observations that administration of endotoxin or cytokines produced a prompt increase in serum leptin in animals and in humans, the authors also related circulating leptin to inflammatory markers. No relationship was found with tumor necrosis factor (TNF) or with soluble TNF-receptor (sTNF-R) levels.17
Schols et al19 recently reported on leptin levels in both subtypes of COPD, emphysema and chronic bronchitis. As expected, emphysema patients had a lower BMI and a lower fat mass than patients with chronic bronchitis. Leptin levels were significantly lower in the emphysematous group. Nondetectable levels of leptin were found in 8 of 27 patients with emphysema (30%), relative to 2 of 18 patients with chronic bronchitis (11%). Leptin was moderately related to fat mass in emphysema and in chronic bronchitis. In absolute terms, as well as adjusted for fat mass, leptin was significantly related to sTNF-R55 in emphysema patients but not in patients with chronic bronchitis. Remarkably, no differences in TNF-receptors could be demonstrated between the two groups.
Both studies suggest a physiologic regulation of leptin, independent of TNF (at least in chronic bronchitis patients), as well as a cytokine-leptin link in emphysematous patients. The exact regulation of leptin needs further exploration in the near future.
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Pathogenesis of Differences in Body Composition in COPD Phenotypes |
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REE can now be adequately and easily assessed by indirect calorimetry. Initially, a lot of attention was focused on assessment of resting or basal energy expenditure in COPD patients, assuming that the contribution of activity-related expenditure would be limited in this group of impaired patients. An increased REE has been reported in different studies.20 In the past, the increase in REE was explained by increases in the work of breathing21 ; however, growing evidence exists that REE reflects the work of breathing22 rather than the level of inflammation in COPD patients.23 24 The limited role of REE on the development of FFM depletion was demonstrated by the data of Creutzberg et al.25 These authors demonstrated a similar distribution of FFM depletion in normometabolic and hypermetabolic COPD patients. This observation was supported by Baarends et al,26 who showed that there was no significant difference in free-living total daily energy expenditure between clinically stable patients with COPD with an elevated REE and those with a normal REE. Variations in total daily energy expenditure reflect differences in expenditure for activities but not for REE. Even in COPD patients with severe airflow limitation, total daily energy expenditure was significantly higher than in healthy subjects.26 These differences can be attributed to a decreased mechanical efficiency in COPD patients.27
Systematic analyses of dietary intake in COPD patients are scarce. Schols et al2 reported an inadequate dietary intake for energy expenditure, especially in the more disabled COPD population. In a recent study, these authors found that sTNF-R55, a marker for inflammation, and leptin were significantly related to dietary intake in absolute terms as well as adjusted for REE.19 The role of systemic inflammation was confirmed by the data of Creutzberg et al,28 demonstrating a significant relationship between baseline dietary intake and soluble intercellular adhesion molecule-1 (Fig 1 ).
A disturbed energy balance, at least in a subgroup of COPD patients, is further supported by the outcome of nutritional intervention studies in COPD patients.29 Despite the positive outcomes of nutritional intervention in the majority of COPD patients, Creutzberg et al28 demonstrated that aging, relative anorexia and elevated systemic inflammatory responses, as assessed by circulating levels of sTNF-R55, are associated with nonresponses to nutritional therapy.
Muscle Protein Degradation in COPD
Depletion of FFM is a prominent finding in COPD patients.
Accelerated muscle proteolysis is considered the primary cause of the
loss of lean body mass, not only in COPD, but also in many other
chronic diseases. Although multiple proteolytic systems that serve
distinct functions are described in mammalian cells, the
ubiquitin-proteasome pathway is the most important in the normal
turnover of most cellular proteins and in the accelerated breakdown of
muscle proteins in catabolic states. The ubiquitin-proteasome pathway
is a multi-enzymatic process of degradation that requires adenosine
5'-triphosphate (ATP).
Activation of the ubiquitin-proteasome pathway has been reported in a variety of models and clinical conditions.30 The regulating role of glucocorticoids on muscle proteolysis is very important. It has been clearly demonstrated, from rats in the fasting state, that glucocorticoids, together with other signals, are required to increase messenger RNAs encoding ubiquitin and proteasome subunits and for ubiquitin-protein conjugates in muscles.31 32 Glucocorticoids not only stimulate proteolysis, but inhibit protein synthesis and the transport of amino acids into the muscle to promote the mobilization of amino acids for gluconeogenesis.
Data of direct effects of inflammatory mediators on differentiated
skeletal muscle cells are limited. Li et al33
studied
underlying mechanisms of TNF-induced effects in differentiated skeletal
muscles. They demonstrated that TNF stimulated time- and
concentration-dependent reductions in total protein content and loss of
myosin heavy chain content. These changes were evident at low TNF
concentrations that did not alter muscle DNA content and were not
associated with a decrease in myosin heavy chain synthesis. This TNF
signal is transduced in part by activation of nuclear factor-kB, a
process that involves ubiquitin conjugation and proteasomal degradation
of inhibitory protein-kB
. There is an urgent need for a better
understanding of the mechanisms and regulation of protein breakdown in
COPD patients to improve treatment prospects.
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Differences in Muscular Adaptation in COPD Subtypes |
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Fiber Type Composition
Fiber types can be classified based on differences in
immunoreactivity for antibodies specific to different myosin heavy
chain (MHC) isoforms. In human muscles, three different MHC isoforms
are expressed: MHC-1, MHC-2A, and MHC-2B. In the same way, myosin light
chain (MLC) isoforms can be determined. The following MLC isoforms can
be discerned: the fast and slow isoforms of regulatory MLC (MLC-2s and
MLC-2f) and three isoforms of alkaline MLC (MLC-1s, MLC-1f, and
MLC-3f). Satta et al34
studied the fiber type composition
of the musculus vastus lateralis in COPD patients. They reported that
the proportion of the fast MHC-2B isoform was increased in patients
with COPD. While diffusing capacity, vital capacity, and
FEV1 were positively correlated with slow MHC
isoform content, only diffusing capacity was negatively correlated with
fast MHC isoform content. The co-ordinated expression between MHC and
MLC isoforms was also altered in COPD patients, suggesting that the
co-ordinated protein expression was lost in the skeletal muscles of
COPD patients. The authors suggest that these changes can partially be
explained by reduced availability of oxygen. An impaired diffusing
capacity is generally considered a feature of emphysema in a COPD
population,13
and arterial oxygen desaturation is a
frequently reported finding in patients with impaired diffusing
capacity.35
Further data on muscle composition are needed
in these COPD subtypes. The hypothetical role of tissue hypoxia also
needs to be explored.
These adaptations of the skeletal muscle toward a predominance of anaerobic glycolytic type 2 muscle fibers affect the aerobic capacity of the muscle and may cause the type 2 predominant muscle to be more prone to fatigue, because anaerobic fibers synthesize ATP less efficiently than aerobic metabolism, and because production of lactic acid is marked higher.36 37 38
Interestingly, opposite changes seem to occur in the diaphragms of patients with COPD. Levine et al39 reported increases of slow MHC-1 and lower percentages of MHC-2A and MHC-2B in diaphragms of COPD patients, suggesting an adaptation that increases resistance to fatigue.
Biochemical Adaptations of Muscle Metabolism in COPD Subtypes
Early lactic acidosis during exercise is reported in a significant
number of COPD patients.40
Maltais et al41
compared the arterial lactic acid kinetics during exercise to the
oxidative capacity of the skeletal muscles in COPD patients. Muscle
biopsies were taken from the musculus vastus lateralis. These authors
reported significantly lower activity of the oxidative enzymes in COPD
patients. Furthermore, the relationship of lactic acid to oxygen
consumption during exercise was significantly related to the
reduced oxidative capacity. Oxidative capacity in this study was
assessed by citrate synthase, catalyzing the first step of the Krebs
cycle, and by 3-hydroxyacyl CoA dehydrogenase, involved in the fatty
acid oxidation. After endurance training, the same authors reported a
significant inverse relationship between the percentage changes in the
activity of citrate synthase and 3-hydroxyacyl CoA dehydrogenase
and the percentage changes in arterial lactic acid during
exercise.42
It remains unclear if the decrease in
oxidative capacity can be attributed to changes in muscle structure or
to intrinsic adaptations of muscle metabolism.
Besides changes in enzyme concentrations, differences in intermediary metabolites can explain differences in lactate kinetics. Engelen et al43 investigated the exercise-induced lactate response in COPD patients, stratified in patients with emphysema and chronic bronchitis, based on high-resolution CT findings. Lactate response in COPD patients was compared with groups of control subjects, physically active and physically inactive. Lactate response to exercise was steeper in the emphysema group than in the chronic bronchitis group or in the physically inactive group. Lactate steepness during exercise was higher in the chronic bronchitis group than in the physically inactive group. A significant linear relationship was found between muscle glutamate (GLU) and lactate steepness during exercise. It can be hypothesized that decreases in muscle GLU can have different effects on lactate metabolism. The decreased GLU concentration can induce a shift in the alanine aminotransferase reaction, resulting in an increase of pyruvate concentration and, secondarily, in lactate concentration. A decrease in alanine aminotransferase activity can also result in a decreased influx of Krebs cycle metabolites, resulting in an impaired Krebs cycle activity. Decreased muscle GLU concentrations in the presence of marked elevated glutamine concentrations in muscle biopsies were reported by Pouw et al.23
Little information is yet available on lactate metabolism in COPD. In general, an increase in lactate production leads to an enhanced liver lactate uptake and an increase in liver gluconeogenesis. However, hypoxia causes a clear inhibition in GLU at the phosphoenolpyruvatekinase level: the transcription of phosphoenolpyruvatekinase is depressed under hypoxic conditions.44 In vivo studies in COPD patients are needed to investigate lactate metabolism.
Lactate might be viewed as a key metabolic event, permitting the metabolism to modify according to hypoxic conditions, as frequently found in patients with COPD. According to this hypothesis, the increased lactate can be considered as a metabolic tool, permitting the oxidation of either lactate or glucose as aerobic substrates, according to a metabolic priority, yet sparing glucose for privileged tissues like the heart.45
Energy and Mitochondrial Metabolism in COPD
In mammals, there is a very tight connection between oxygen
consumption and ATP production and utilization; 90% of oxygen
consumption is responsible for 90% of ATP synthesis, and 10% of ATP
synthesis in our body is independent of oxygen. Under normal
conditions, the rate of oxygen delivery to the cell must be precisely
adjusted to avoid excessive free radical production. The mitochondrial
respiratory chain is an essential element in the transduction of energy
during life. Mitochondria occupy a pivotal position in aerobic ATP
reduction through oxidative phosphorylation of adenosine diphosphate
(ADP). All energy-producing reactions generate reducing equivalents in
the form of reduced nicotinamide adenine dinucleotide (NADH) and
reducing flavins, which are ultimately oxidized by oxygen through a
chain of oxidoreduction reactions occurring in complexes that reside in
the inner mitochondrial membrane.46
This process of
oxidative phosphorylation is pushed by the redox potential (NADH/NAD)
and is limited by the phosphate potential (ATP/ADP.Pi).
Experimental data on muscle energy and mitochondrial metabolism in patients with stable COPD are scarce. A recent study reported on subcellular adaptations of the human diaphragm in patients with COPD.47 Patients suffering from COPD showed a higher mitochondrial density than subjects without airways obstruction. Furthermore, an inverse correlation was found between the degree of airways obstruction and mitochondrial density. Mitochondrial density was directly related to the level of hyperinflation and indirectly related to respiratory muscle function. In addition, clusters of mitochondria as well as mitochondrial paracrystalline inclusions were frequently found in COPD patients. These changes in the concentration of energetic organelles are in accordance with a persistent mechanical overload of the respiratory muscles, while the presence of paracrystalline inclusions probably reflect metabolic mismatching in the mitochondria. Sauleda et al48 reported that COPD patients with chronic respiratory failure showed increased cytochrome oxidase (COX) activity, and that COX activity was inversely related to arterial oxygen tension. However, COX messenger RNA was not different between patients and control subjects. These data suggest adaptations of COX muscle activity under hypoxemic conditions, regulated at the translational level by increasing the number of mitochondrial ribosomes.
The application of 31 P-nuclear magnetic resonance has enabled a direct and noninvasive assessment of tissue levels of high-energy phosphates and pH, even under dynamic conditions such as exercise testing. High levels of ATP, creatine phosphate (PCr) and NADH reflect a high energy state, whereas elevated levels of ADP, adenosine monophosphate, inorganic phosphate (Pi) and oxidized NAD commonly reflect a low energy state. The PCr/Pi ratio or phosphorylation potential is an important measure of the energy status of the cell and can be used to determine the adequacy of energy reserves for vital functions. The PCr/Pi ratio is thought to be closely related to the ATP/ADP ratio, and a reduction of the ratio reflects an impairment in the oxidative metabolism of the muscle. Energy-rich phosphagens can also be analyzed in muscle samples obtained by muscle biopsy.
Most striking are the reduced levels of the high energy phosphates in rest observed in COPD patients. Pouw et al49 found a lower phosphocreatine/creatine ratio and a lower ATP/ADP ratio in COPD patients. Furthermore, she reported that inosine monophosphate levels (IMP) were slightly, but statistically significantly elevated in COPD patients. The latter may be due to increased degradation of accumulating adenosine monophosphate by deamination, which probably reflects reduced aerobic capacity.50 Remarkably, IMP-positive COPD patients were characterized by a significantly lower diffusing capacity. IMP levels were negatively related to the ATP/ADP ratio, suggesting an imbalance between ATP utilization and resynthesis. The insufficient energy supply is even more prominent during exercise–a marked drop in the PCr/Pi ratio and a fast drop in pH were found in the calf muscles of COPD patients51 52 53 performing exercise, and similar results were obtained in the forearm muscles.54 55 56 57
Marked acidification of the exercising muscle demonstrates lactate accumulation. Nuclear magnetic resonance studies also have demonstrated a delayed recovery of PCr/Pi ratio and of pH in COPD patients.57 Besides intrinsic changes in muscle metabolism, contributing to impaired aerobic capacity, an increased percentage of type 2B fiber contributes to a reduced PCr/Pi during exercise and delays recovery of PCr/Pi after exercise.52 57 Further data are needed to unravel the disturbed energy supply in COPD in view of the metabolic alterations, the shifts in fiber composition, and the subcellular changes in COPD.
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Conclusion |
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