The primary goal of this study was to determine first whether REE was increased in patients with COPD and second, whether this was associated with increased protein turnover and/or systemic inflammation relative to the values of healthy controls. We found that COPD subjects had loss of FFM even with preservation of BMI. Furthermore, our results show that as a group, COPD subjects had increased REE and faster rates of protein breakdown and synthesis compared with controls. Protein catabolism was not significantly different between the groups. There were no differences in the plasma concentrations of the inflammatory markers TNF-α, CRP and IL-6 between COPD subjects and controls, although the variability in the concentrations was high and the sample size was small. These findings suggest that increased REE and protein turnover are involved in the loss of FFM in patients with severe COPD.
To negate the influence that the different body composition of the three groups of subjects may have on the metabolic measurements, REE and protein kinetics were expressed per unit of fat-free mass, a proxy for body cell mass. All but 1 subject with COPD in this study had low FFMI. The low FFM of this sample may be related to the severity of COPD, since previous studies have shown that FFMI is associated with the degree of airflow obstruction [15
], with highest prevalence of cachexia (defined as low BMI and low FFMI) in GOLD Stage IV disease [12
]. FFM was a major determinant of REE in the COPD subjects. This is in accordance with population studies showing that FFM is the major determinant of REE [16
]. Our finding of a greater REE in COPD subjects compared to controls after adjustment for FFM is in agreement with earlier findings [4
], and strongly suggests that COPD is associated with hypermetabolism. Even the COPD subjects with low BMI, who should have a lower REE due to the hypometabolic adaptation to undernutrition [18
], had an REE that was 18% greater than that of the controls. Though reduced dietary energy may also be a contributing factor in the weight loss of COPD, most nutritional studies have reported that the measured dietary energy intake of COPD subjects, including those who have not lost weight, is greater than their recommended energy requirement [19
], suggesting a compensatory response to an elevated energy requirement.
Alterations in metabolic processes that consume energy may also contribute to an increased REE in COPD. Because synthesis and breakdown of muscle protein are primarily responsible for the energy expenditure of resting muscle [8
], increased whole body protein breakdown and synthesis in COPD may be contributing significantly to the higher REE. In COPD subjects, we found that whole body protein breakdown and synthesis rates are faster than in controls. These results corroborate the findings of an earlier study using a different tracer approach [10
]. Engelen et al found increased whole-body protein synthesis and breakdown when using phenylalanine, but not leucine tracers. However, leucine oxidation was not measured, and KICA was not used as a surrogate for intracellular leucine, which may have affected the results [21
]. In support of protein synthesis and breakdown contributing to the increased REE of COPD, there was a significant correlation between REE and both the rate of protein breakdown and the rate of protein synthesis in all subjects.
Both this study and the prior study by Engelen et al (11) failed to show a significant difference in net protein loss (leucine oxidation in this study) between COPD and control subjects. This was unexpected, because muscle protein wasting can only occur when there is an increase in net protein catabolism. There are several possible explanations for this unexpected finding. First, both studies were performed in the fasted state only, when there is usually a downregulation of amino acid oxidation and ureagenesis in an attempt to conserve protein [22
]. This is not true in the fed state. Hence, one cannot rule out the possibility that a difference in protein catabolism between COPD subjects and controls does exist in the fed state. Second, because both studies were performed when the patients were clinically stable, the actual period of protein loss, such as during exacerbation, may have been missed. When divided by BMI, the mean leucine oxidation of the COPD subjects with low BMI was actually similar to the mean value of the seven control subjects, suggesting that these patients may have already established a new homeostasis between protein breakdown and synthesis to conserve body protein content. On the other hand, the subjects with preserved BMI but with low FFMI were probably still losing muscle mass, and they had mean leucine oxidation that was 24% faster than the mean value of the controls. Finally, measurement of leucine oxidation may not accurately reflect protein catabolism if there is an adaptation to restrain oxidation of branch chain amino acids, by downregulation of branched-chain aminotransferase and branched-chain α-keto acid dehydrogenase, in an attempt to maintain their availability for protein synthesis, thereby slowing down protein loss in COPD patients..
The protein metabolic response and body composition were different in the two groups of COPD subjects. The majority of subjects with preserved BMI had low FFMI, indicating selective loss of FFM. On the other hand, subjects with low BMI had low FFM and FM, indicating loss of both fat and muscle. Whole-body protein breakdown was higher in the COPD group with preserved BMI than in both controls and COPD subjects with low BMI. These results suggest that while the selective loss of FFM may be associated with increased whole-body protein breakdown, loss of both FFM and FM may represent a distinct metabolic syndrome.
This study was limited by the use of the leucine tracer technique to measure whole-body protein turnover instead of muscle protein synthesis and breakdown rates. Although the 13
C-leucine tracer method is considered the reference method to estimate whole-body protein metabolism in most conditions, it may not have been the most ideal method to use in this study, because it does not provide specific information on muscle protein synthesis and breakdown rates. Obtaining fractional muscle protein synthesis rate in the current 13
C-leucine tracer infusion protocol would have required timed skeletal muscle biopsies, which were not performed in this study. Further, muscle protein breakdown rate could have been easily estimated by co-infusing, 2
-3-methylhistidine to calculate 3-methylhistidine flux as an index of myofibrillar protein breakdown rate [23
]. Alternatively, the pulse tracer injection of L-[ring
]phenylalanine and L-[ring
N]phenylalanine could have been used to measure muscle protein fractional synthesis and breakdown rates simultaneously as described by Zhang XJ et al [24
]. We plan to use this approach in future studies to address muscle protein metabolism in COPD.
Our findings of an increased REE and protein turnover in the COPD patients point towards the presence of systemic inflammation. However, given the wide range of concentrations of the inflammatory markers, this study was underpowered to detect a difference between groups. Furthermore, the controls were current and former smokers, and smoking even in the absence of lung disease can lead to systemic inflammation. A study of current and former smokers demonstrated that 20.6% of those subjects without COPD had CRP between 3–10 mg/L and 5.2% had CRP > 10 (26). Current and former smokers have also been found to have increased concentrations of IL-6 compared to non-smokers (27). Smoking can also affect protein turnover. Petersen et al found that whole-body leucine flux was similar between smoker and non-smokers, but mixed muscle protein fractional synthesis rate was significantly less in smokers compared to nonsmokers [25
]. However, all COPD subjects were also current or former smokers, yet they had increased, rather than decreased, whole-body protein synthesis. This finding suggests that the presence of COPD affects protein turnover independent of smoking.
This is the first study to investigate the link between REE and protein turnover in patients with severe COPD. However, the study is limited by a small sample size. It is possible that this subgroup of COPD patients is not representative of the disease as a whole, since COPD is a very heterogeneous disease. Furthermore, use of 13C-leucine as a tracer allows for estimation of whole-body protein breakdown, but does not specifically measure skeletal muscle protein synthesis.
In summary, subjects with COPD have increased REE and increased whole-body protein synthesis and protein breakdown when compared to controls. Because protein synthesis and breakdown are a major component of REE, increased protein turnover may be a major contributor to a higher REE in COPD. In addition, COPD subjects with low BMI and those with preserved BMI appear to have different metabolic changes, which may be contributing to different body composition in these two groups. Finally, our findings of a higher REE in all COPD subjects, together with changes in protein turnover, strongly suggest that supplemental dietary energy and protein should be part of routine therapy even in those COPD patients with normal BMIs.