Catabolic/Anabolic Balance and Muscle
Wasting in Patients With COPD*
Richard Debigaré, PhD; Karine Marquis, MSc; Claude H. Côté, PhD;
Roland R. Tremblay, MD, PhD; Annie Michaud, MSc; Pierre LeBlanc, MD; and
François Maltais, MD
Backgroud: The mechanisms leading to muscle wasting in patients with COPD are still uncertain.
This study was undertaken to evaluate the relationships among circulating levels of catabolic
factors (ie, interleukin [IL]-6 and cortisol), anabolic factors (ie, bioavailable testosterone [Tbio],
dehydroepiandrosterone sulfate [DHEAS], and insulin-like growth factor [IGF]-I), and mid-thigh
muscle cross-sectional area (MTCSA) in patients with COPD.
Methods: Serum levels of the above factors were measured in 45 men with COPD (mean [ⴞ SEM]
FEV1, 43 ⴞ 3% predicted; mean age, 67 ⴞ 1 years) and 16 sedentary healthy men of similar age.
MTCSA was quantified using CT scanning. Patients with COPD were subdivided into two groups
according to the MTCSA (< 70 or > 70 cm2).
Results: There was a greater prevalence of hypogonadism (ie, Tbio, < 2 nmol/L) in patients with
COPD compared to control subjects (22% vs 0%, respectively). Patients with an MTCSA of
< 70 cm2 had significantly reduced levels of DHEAS compared to those in healthy subjects
(p < 0.01). IL-6 levels were significantly higher in both subgroups of COPD patients compared to
those in control subjects (p < 0.005). The cortisol/DHEAS, IL-6/DHEAS, IL-6/Tbio, and IL-6/
IGF-I ratios were significantly greater in COPD patients with an MTCSA of < 70 cm2 compared
to those in control subjects (p < 0.05). The cortisol/DHEAS and IL-6/DHEAS ratios were also
significantly greater in COPD patients with an MTCSA of < 70 cm2 than in COPD patients with
an MTCSA of > 70 cm2 (p < 0.05). In a stepwise multiple regression analysis, the IL-6/DHEAS
ratio explained 20% of the variance in MTCSA (p < 0.005).
Conclusion: Catabolic/anabolic disturbances were found in COPD patients leading to a shift
toward catabolism and possibly to the development of peripheral muscle wasting.
(CHEST 2003; 124:83– 89)
Key words: atrophy; COPD; cytokines; insulin-like growth factor-I; muscle; testosterone; wasting
Abbreviations: BMI ⫽ body mass index; DHEA ⫽ dehydroepiandrosterone; DHEAS ⫽ dehydroepiandrosterone
sulfate; IGF ⫽ insulin-like growth factor; IL ⫽ interleukin; LH ⫽ luteinizing hormone; MTCSA ⫽ mid-thigh muscle
cross-sectional area; Tbio ⫽ bioavailable testosterone; TNF ⫽ tumor necrosis factor; TNF-R ⫽ tumor necrosis factor
receptor
t is now recognized that peripheral muscle dysfuncI tion
adversely affects clinical outcomes in COPD.
1
Concomitantly with muscle structural changes,2 there
is a loss of peripheral muscle mass in patients with this
disease,3 often despite having a normal body mass
index (BMI).3 Peripheral muscle wasting in COPD
patients is associated with muscle weakness,3 decreased
exercise capacity,3,4 impaired quality of life,5 and more
importantly, decreased survival.6 Although a gain in
*From the Centre de Recherche (Drs. Debigaré, LeBlanc, and
Maltais, and Ms. Marquis and Ms. Michaud), Hôpital Laval,
Institut Universitaire de Cardiologie et de Pneumologie, and the
Centre de Recherche du Centre Hospitalier Universitaire de
Quebéc Pavillon Centre Hospitalier de l’Université Laval (Drs.
Côté and Tremblay), Université Laval, Sainte-Foy, QC, Canada.
Dr. Debigaré was a recipient of a PhD training award of the
Fonds de la Recherche en Santé du Québec. Dr. Maltais is a
research scholar of the Fonds de la Recherche en Santé du
Québec. This research has been supported by Canadian Institutes of Health Research grant No. 36331.
peripheral muscle mass can be obtained with exercise
training7 or anabolic drug supplementation,8 the magnitude of the improvement remains modest. A major
issue is that no clear mechanistic explanations have
For editorial comment see page 1
been proposed to explain how muscle wasting takes
place in COPD patients.
Chronic diseases lead to hormonal dysfunction9
and increased levels of circulatory proinflammatory
Manuscript received August 28, 2002; revision accepted January
7, 2003.
Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (e-mail:
[email protected]).
Correspondence to: François Maltais, MD, Centre de Pneumologie, Hôpital Laval, 2725 Chemin Ste-Foy, Ste-Foy, QC, Canada,
G1V 4G5
www.chestjournal.org
Downloaded From: http://publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21996/ on 06/15/2017
CHEST / 124 / 1 / JULY, 2003
83
cytokines,10 leading to a shift toward catabolism and
eventually to the significant loss of muscle tissue.10
Proinflammatory cytokines such as tumor necrosis
factor (TNF) and interleukin (IL)-6 can induce
muscle wasting in animals,11 and there are also data
For related article see page 75
to support their roles in human cachexia.10 Elevated
blood levels of various proinflammatory cytokines
have been reported in patients with several chronic
diseases that are associated with wasting, including
COPD,12 chronic heart failure,13 and cystic fibrosis.14 Low levels of anabolic steroids and growth
factors15 also can contribute to the wasting process in
patients with chronic diseases. Low levels of testosterone16 and insulin-like growth factor (IGF)-I17
already have been reported in COPD patients, but
how this relates to muscle wasting has not been
evaluated. Alterations in adrenal hormone metabolism also have been proposed to contribute to the
wasting process in patients with chronic heart failure.18 Reduced levels of dehydroepiandrosterone
(DHEA), an adrenal steroid, and a high cortisol/
DHEA ratio are thought to create an imbalance
between protein synthesis and degradation favoring
catabolism over anabolism in patients with this disease.18 The potential role of the adrenal hormones in
wasting associated with COPD has not been investigated.
At the molecular level, the maintenance of muscle
mass is dependent on several intricate and redundant
regulating pathways, and it is unlikely that disturbances
in one single component of this complex system explain
entirely the wasting process. In this regard, the interaction between catabolic and anabolic factors is interesting to consider. For instance, a low anabolic hormone level may synergize the catabolic effects of
proinflammatory cytokines.19 Conversely, high anabolic
hormone level may protect against the potentially
negative impact of proinflammatory cytokines on muscle mass as exemplified in highly trained athletes in
whom bursts of proinflammatory cytokines after a
high-intensity activity do not lead to muscle wasting.20
Thus, investigating the balance between anabolic and
catabolic factors may be more informative than individual anabolic and catabolic factors that are studied in an
isolated fashion.
We have recently confirmed the important harmful prognostic implication of a reduced muscle mass
on survival in patients with COPD.6 This was particularly true in patients with an FEV1 ⬍ 50% of
predicted in whom a mid-thigh muscle crosssectional area (MTCSA) of ⬍ 70 cm2 was associated
with a fourfold increase in mortality rate. The
present study concerns a subset of these patients in
whom blood was available to evaluate the relationships between blood levels of catabolic factors (ie,
IL-6, TNF, and cortisol) and anabolic factors (ie,
bioavailable testosterone [Tbio], DHEA sulfate
[DHEAS], and IGF-I), and peripheral muscle wasting. The ratio between cortisol and DHEAS was
taken as an index of adrenal steroid metabolism,
while the ratios of IL-6 and the anabolic factors were
used as markers of the catabolic/anabolic balance in
these subjects.
Materials and Methods
Subjects
The study population consisted of 45 men with COPD who
were in stable condition, who had participated in our previous
study6 evaluating the impact of low muscle mass on survival in
COPD, and in whom blood was available for the quantification
of anabolic and catabolic factors. The diagnosis of COPD was
based on smoking history and on pulmonary function test
results showing irreversible airflow limitation.21 Patients with
any active inflammatory diseases as well as any other chronic
diseases, such as chronic heart failure or diabetes, were
excluded from the study. No patients were receiving long-term
oxygen therapy, and none had been exposed to systemic
corticosteroids in the 6-month period preceding this study.
Sixteen sedentary, healthy men who were ex-smokers and
were of similar ages were recruited by means of a newspaper
advertisement, and served as control subjects for biochemical
markers. These subjects were free of any medication, and
none reported a significant drinking history. They were evaluated by a physician who was involved in the present study to
confirm their healthy status. The institutional ethics committee approved the research protocol, and written consent was
obtained in each case.
Protocol
Anthropometric Measurements and Pulmonary Function Tests:
After height and weight were measured, standard pulmonary
function tests, including those for spirometry, lung volumes, and
diffusion capacity, were performed, and the results were compared to normal values reported in the studies of Knudson et al,22
Goldman and Becklake,23 and Cotes and Hall,24 respectively. For
control subjects, only spirometry values were obtained.
CT Scan of the Thigh: In order to evaluate MTCSA, a CT scan
of the right thigh halfway between the pubic symphisis and the
inferior condyle of the femur was performed, as previously
described.3
Blood Sampling and Analysis: After a resting period of 30 min,
antecubital venous blood was sampled between 8:00 am and
9:00 am in overnight fasted subjects. Blood was centrifuged for
15 min, put into aliquots, and stored at ⫺80°C until further
analysis. Commercial immunoassays were used to measure the
serum levels of luteinizing hormone (LH) [Axsym; Abbot Laboratories; Abbot Park, IL] and cortisol (Elecsys 1010; Roche
Diagnostics; Basel, Switzerland), while serum levels of Tbio and
DHEAS were determined using a commercial radioimmunoassay
(Coat-A-Count Testosterone and Coat-A-Count DHEA-SO4, respectively; Diagnostic Products Corporation; Los Angeles, CA).
Tbio dosage was preceded by an ammonium sulfate precipitation
84
Downloaded From: http://publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21996/ on 06/15/2017
Clinical Investigations
of sex hormone-binding globulin-bound testosterone, as previously described.25 The intraassay and interassay coefficients of
variation were as follows: LH, 6.6% and 6.4%, respectively;
cortisol, 3.2% and 5.6%, respectively; Tbio, 7.4% and 15.5%,
respectively; and DHEAS, 5.3% and 6.3%, respectively. Blood
serum levels of IL-6, TNF, TNF receptor (TNF-R) 55, TNFR75, and IGF-I were determined using commercial enzymelinked immunosorbent assay kits (R&D Systems; Minneapolis,
MN) with limits of detection at 0.094 pg/mL, 0.12 pg/mL, 3.0
pg/mL, 1.0 pg/mL, and 0.026 ng/mL, respectively.
Statistical Analysis
Blood samples and CT scans were analyzed without knowledge of
the clinical status. All data are reported as the mean (SEM). In order
to evaluate the relationship between catabolic and anabolic factors,
and peripheral muscle mass, patients with COPD were subdivided
according to their MTCSA, using a cut point of 70 cm2, according to
Marquis et al.6 In that study, an MTCSA of ⬍ 70 cm2 was strongly
associated with mortality in COPD patients. Analysis of variance and
post hoc Tukey comparison tests were used to compare COPD
subgroups and control subjects. Simple linear regressions were
performed in order to evaluate the possible relationships between
catabolic and anabolic factors, and peripheral muscle mass. In
COPD, a stepwise multiple regression analysis was performed with
MTCSA as the dependent variable and age, FEV1 % predicted,
Tbio, DHEAS, IGF-I, cortisol, IL-6, cortisol/DHEAS ratio, IL-6/
Tbio ratio, IL-6/DHEAS ratio, and IL-6/IGF-I ratio as the independent variables. A p value of ⬍ 0.05 was considered to be statistically
significant.
Results
The anthropometric characteristics of both subgroups of patients and control subjects are shown in
Table 1. Twenty-seven patients with COPD had an
MTCSA of ⱖ 70 cm2 (86 ⫾ 2 cm2), while the remaining 18 patients had an MTCSA of ⬍ 70 cm2
(58 ⫾ 2 cm2). For comparison, the mean MTCSA in
the 16 healthy individuals was 96 ⫾ 4 cm2. Patients
with an MTCSA of ⬍ 70 cm2 had a significantly
lower BMI compared to patients with an MTCSA of
ⱖ 70 cm2 and subjects in the control group. The
impairment in pulmonary function, Pao2 and Paco2
was similar in both groups of COPD patients.
The blood levels of catabolic and anabolic factors
in control subjects and patients with COPD expressed in absolute and relative values are provided
in Table 2 and Figure 1, top, A, respectively. Tbio
levels were similar between groups (p ⬎ 0.05)
and were within the normal range for men of
the sixth decade (mean level, 3.3 nmol/L; SEM,
1.3 nmol/L).25 However, 6 of 27 patients (22%) with
an MTCSA of ⱖ 70 cm2 and 4 of 18 patients (22%)
with an MTCSA of ⬍ 70 cm2 could be classified as
hypogonadic, which was defined as a Tbio level of
⬍ 2 nmol/L,25 while the levels of none of the control
subjects were below this level. Of the 10 hypogonadic patients, 7 patients had low or normal levels of
LH, suggesting an hypogonadotrophic hypogonadism, while the remaining 3 patients had appropriate
elevations of LH, suggesting a testicular dysfunction.
Patients with an MTCSA of ⬍ 70 cm2 had significantly reduced levels of DHEAS compared to control subjects (p ⬍ 0.01). The group mean values for
LH, cortisol, IGF-1, TNF, TNF-R55, and TNF-R75
were not significantly different among the three
groups. IL-6 levels were significantly higher in both
subgroups of COPD patients compared to those in
control subjects (p ⬍ 0.005), but the levels were not
significantly different between the COPD subgroups. Among all subjects, IL-6 was negatively
correlated with Tbio (r ⫽ ⫺0.33; p ⫽ 0.01) and
DHEAS (r ⫽ ⫺0.38; p ⫽ 0.0035).
The pattern of adrenal steroid metabolism and the
Table 1—Subject Characteristics*
COPD Patients
Variables
Age, yr
BMI
FEV1
L
% predicted
FEV1/FVC, %
TLC, % predicted
Dlco, % predicted
Pao2, mm Hg
Paco2, mm Hg
MTCSA, cm2
Control Subjects
(n ⫽ 16)
65 (1)
28 (1)
3.10 (0.24)
100 (5)
76 (3)
96 (4)§
MTCSA ⱖ 70 cm
(n ⫽ 27)
MTCSA ⬍ 70 cm2
(n ⫽ 18)
2
67 (1)
28 (1)
68 (2)
23 (1)†
1.24 (0.10)‡
44 (3)‡
45 (2)‡
115 (3)
77 (5)
81.2 (2.3)
39.8 (0.8)
86 (2)§
1.14 (0.17)‡
40 (5)‡
44 (3)‡
115 (6)
71 (9)
79.7 (3.0)
39.8 (0.8)
58 (2)§
*TLC ⫽ total lung capacity; Dlco ⫽ diffusing capacity of the lung for carbon monoxide. Values are mean (SEM).
†p ⬍ 0.05 vs control subjects and COPD patients with MTCSA ⱖ 70 cm2.
‡p ⬍ 0.01 vs control subjects.
§p ⬍ 0.05 vs the two other groups.
www.chestjournal.org
Downloaded From: http://publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21996/ on 06/15/2017
CHEST / 124 / 1 / JULY, 2003
85
Table 2—Serum Levels of Anabolic and Catabolic Factors*
COPD Patients
Factors
Control Subjects
(n ⫽ 16)
MTCSA ⱖ 70 cm2
(n ⫽ 27)
MTCSA ⬍ 70 cm2
(n ⫽ 18)
Tbio, nmol/L
LH, U/L
DHEAS, ␮mol/L
Cortisol, nmol/L
IGF-I, ng/mL
IL-6, pg/mL
TNF, pg/mL
TNF-R55, pg/mL
TNF-R75, pg/mL
3.3 (0.3)
5.4 (0.6)
3.0 (0.3)
340 (18)
81 (6)
2.1 (0.3)
3.45 (0.23)
1611 (93)
3047 (117)
3.0 (0.2)
5.8 (0.8)
2.5 (0.3)
363 (22)
74 (5)
4.6 (0.6)‡
3.03 (0.13)
1719 (95)
3222 (131)
3.3 (0.4)
6.0 (0.8)
1.6 (0.3)†
332 (29)
72 (9)
5.4 (0.8)‡
3.53 (0.41)
1873 (334)
3211 (230)
*Values given as the mean (SEM).
†p ⬍ 0.01 vs control subjects and COPD patients with MTCSA ⱖ 70 cm2.
‡p ⬍ 0.005 vs control subjects.
values for catabolic/anabolic ratios expressed as percentages of the control values are shown in Figure 1,
bottom, B. In general, the magnitude of these ratios
increased with the level of muscle atrophy. The
adrenal steroid metabolism was altered in COPD
patients with an MTCSA of ⬍ 70 cm2, as indicated
by a greater cortisol/DHEAS ratio compared to
control subjects and COPD patients with an MTCSA
of ⱖ 70 cm2 (p ⬍ 0.01). The IL-6/Tbio ratio, IL-6/
DHEAS ratio, and IL-6/IGF-1 ratio were significantly greater in COPD patients with an MTCSA of
⬍ 70 cm2 compared to control subjects (p ⬍ 0.05).
The IL-6/DHEAS ratio was also significantly greater
in COPD patients with an MTCSA of ⬍ 70 cm2 than
in COPD patients with an MTCSA of ⱖ 70 cm2
(p ⬍ 0.05). The IL-6/Tbio ratio and IL-6/IGF-1 ratio
were significantly greater in COPD patients with an
MTCSA of ⱖ 70 cm2 than in control subjects
(p ⬍ 0.05). None of the ratios involving TNF, TNFR55, and TNF-R75 were significantly different
among the three groups.
Univariate analysis indicated that only the IL-6/
DHEAS ratio (r ⫽ ⫺0.40; p ⬍ 0.01) was significantly correlated with MTCSA. There was no correlation between any of the catabolic and anabolic
factors taken individually and MTCSA. No significant correlation was found between BMI and any
catabolic and anabolic factors taken individually or
any of the catabolic/anabolic factor ratios. In a
stepwise multiple regression analysis, the IL-6/
DHEAS ratio explained 20% of the variance in
MTCSA (p ⬍ 0.005). The addition of any other
variable in the analysis did not significantly improve
the ability of this model to predict MTCSA.
and not with the level of impairment in lung function. Marked elevations of catabolic/anabolic factor
ratios (ie, cortisol/DHEAS, IL-6/Tbio, IL-6/DHEAS,
and IL-6/IGF-1), particularly in patients with COPD
and low MTCSAs, indicate that there was a shift toward
catabolism in COPD patients. Although none of the
catabolic or anabolic factors were related to MTCSA,
IL-6/DHEAS ratio, which is a marker of the catabolic/
anabolic balance, was found to be a significant correlate
of MTCSA.
Catabolic Factors
Consistent with the results of previous studies,12
IL-6 blood levels were significantly elevated in patients with COPD compared to those in healthy
subjects. IL-6 is a proinflammatory cytokine that is
involved in the induction of the acute inflammatory
response and the induction of B-lymphocyte proliferation and differentiation.26 At the muscle level,
IL-6 is able to initiate catabolism by activating
proteolysis through the ubiquitin proteasome pathway.27 Interestingly, there appears to be a regulating
loop between proinflammatory cytokines and anabolic steroids. Increased levels of proinflammatory
cytokines reduce testosterone secretion by interfering with Leydig cell function.28 Furthermore, anabolic hormone deficiency contributes to elevated
IL-6 levels since the expression of this cytokine is
down-regulated by testosterone and DHEAS.29 The
interactions between cytokines and anabolic steroids
in our patients were supported by the negative
correlation between IL-6, on the one hand, and Tbio
and DHEAS, on the other hand.
Anabolic Factors
Discussion
In this study, peripheral muscle atrophy was associated with disturbances in catabolism and anabolism
The prevalence of hypogonadism in COPD patients in the present study was lower than that
previously reported.17 This can be explained by the
86
Downloaded From: http://publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21996/ on 06/15/2017
Clinical Investigations
Figure 1. Group mean values of serum levels of individual anabolic and catabolic factors (top, A) and
catabolic/anabolic ratios (bottom, B) expressed as a percentage of control values. The serum DHEAS level
was significantly reduced in COPD patients with an MTCSA of ⬍ 70 cm2 compared to control subjects,
while IL-6 serum levels were significantly increased in both patient subgroups. The adrenal steroid
metabolism was altered in COPD patients with an MTCSA of ⬍ 70 cm2, as indicated by a greater
cortisol/DHEAS ratio compared to control subjects and COPD with an MTCSA of ⱖ 70 cm2. The
IL-6/DHEAS, IL-6/Tbio, and IL-6/IGF-I ratios were significantly greater in COPD patients with an
MTCSA of ⬍ 70 cm2 compared to control subjects. The cortisol/DHEAS and IL-6/DHEAS ratios were also
significantly greater in COPD patients with an MTCSA of ⬍ 70 cm2 than in COPD patients with an
MTCSA of ⱖ 70 cm2. Values are given as the mean ⫾ SEM. * ⫽ p ⬍ 0.01; † ⫽ p ⬍ 0.005; ‡ ⫽ p ⬍ 0.05.
absence of chronic hypoxemia or the lack of use of
systemic steroids in our patients, two factors interfering with proper gonadal function. A marked reduction in DHEAS also was found in patients with
an MTCSA of ⬍ 70 cm2. DHEAS is the sulfated
metabolite of DHEA, which is produced by the
adrenal glands and is the most abundant steroid
present in the blood. DHEAS may act directly at the
tissue level or after conversion to androstenedione or
androstenediol, and finally to testosterone. Testos-
www.chestjournal.org
Downloaded From: http://publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21996/ on 06/15/2017
CHEST / 124 / 1 / JULY, 2003
87
terone and DHEAS exert their anabolic actions on
skeletal muscle through several mechanisms. Testosterone increases net protein synthesis within the
muscle using the intracellular amino acid pool.30 In
aging men and women, DHEAS may contribute to
anabolism indirectly by increasing serum IGF-I levels,31 although the discovery of specific binding sites
for DHEAS on skeletal muscle cells supports a direct
action of DHEAS on these cells.32
In our patients, low blood testosterone levels could
be explained by a disturbance in the hypothalamicpituitary axis (ie, low or normal LH values) or at the
gonadal level (ie, high LH values), although the exact
nature of these disturbances remains to be elucidated. Low Pao233 and systemic use of corticosteroids16 can alter the function of the hypothalamicpituitary axis, but these factors did not seem to play
a role in our patients. As mentioned above, the direct
effects of proinflammatory cytokines on the testis
may lead to decreased testosterone production.28
Leydig cell atrophy has been reported in COPD
patients and also may contribute to low testosterone
production.34
IGF-I has been implicated in several important
functions such as cell differentiation, growth, and
maintenance of skeletal muscle. Despite the fact
that similar serum levels of IGF-I were observed
in control subjects and both subgroups of patients,
a possible role for this system in COPD-associated
muscle atrophy cannot be excluded. For instance,
the availability and biological effects of IGF-I may
be modulated by IGF-binding proteins, and it is
conceivable that alterations in the circulating levels of these binding proteins may have decreased
the bioavailability of IGF-I in COPD patients.35
Interestingly, an increased level of IL-6 can exert
a suppressive action on IGF-I by up-regulating the
expression of IGF binding protein-1.36 Alternatively, abnormal interactions with the cell surface
receptor may hamper the proper action of IGF-I
on muscle.
Interactions Between Catabolic and Anabolic
Factors and Muscle Wasting
The absence of correlation between any catabolic
or anabolic factor and MTCSA may seem to deny
their potential role in muscle wasting in COPD
patients. However, this finding is not unexpected,
considering that muscle homeostasis is extremely
complex and may be influenced by several factors
other than the hormonal milieu such as age, level of
physical activity, and the nutritional status. Despite
this, the progressive rise in catabolic/anabolic ratios
with worsening of muscle atrophy (Fig 1, bottom, B)
is quite striking and supports the idea that wasting is
a cumulative effect of a long-term exposure to an
abnormal hormonal milieu. The stepwise regression
analysis showing that the IL-6/DHEAS ratio was the
only significant correlate of MTCSA also illustrates
that evaluating the balance between catabolism and
anabolism may be more relevant to muscle wasting
than looking at individual changes in any catabolic/
anabolic factor. Interestingly, a disruption in the
normal balance between catabolism and anabolism
also has been associated with the occurrence of
cachexia in patients with chronic heart failure.18,37
Taken together, the available information suggests
that the evaluation of the catabolic/anabolic balance
and the interaction between catabolic and anabolic
factors should be considered when evaluating muscle
atrophy in chronic diseases. Another important finding of the present study is that muscle wasting in
COPD patients cannot be predicted by the level of
impairment in lung function. Rather, patients with
an MTCSA of ⬍ 70 cm2 can be differentiated from
those with an MTCSA of ⱖ 70 cm2 on the basis of
greater disturbances in the hormonal determinants
of catabolism and anabolism. Conceivably, the catabolic/anabolic imbalance may influence the clinical
picture and perhaps the survival of patients with
COPD,6 offering a valid target for future therapeutic
interventions.
Limitations of the Study
Although a biological link between catabolic/anabolic disturbances and muscle wasting is plausible,
the correlation between the serum level IL-6/
DHEAS ratio and MTCSA does not necessarily
imply a causal relationship. In this regard, longitudinal studies evaluating long-term changes in the
anabolic/catabolic balance and muscle mass will be
useful. The activities of the different catabolic and
anabolic factors also should be evaluated at the
muscle level. In this study, serum levels of catabolic
and anabolic factors were evaluated on only one
occasion, and, to avoid any bias, this was done at the
same time in the morning. Although speculative,
daily fluctuations in the blood levels of these factors
may occur such that serial sampling could have
provided a better overview of the cytokine and
hormonal abnormalities in COPD patients than
could a single evaluation.
In summary, several abnormalities in catabolic and
anabolic mediators resulting in a shift toward catabolism were found in patients with COPD showing
peripheral muscle atrophy. Although this catabolic/
anabolic imbalance is a likely contributor to the
wasting process in COPD patients, further work is
necessary to evaluate the action of catabolic and
anabolic factors at the muscle level.
88
Downloaded From: http://publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21996/ on 06/15/2017
Clinical Investigations
ACKNOWLEDGMENTS: The authors acknowledge the contribution of Fernand Bertrand for his assistance in biochemical
measurements, and the technical support of Marthe Bélanger,
Marie-Josée Breton, and Brigitte Jean in accomplishing this
study. The authors also thank Drs. Yves Deshaies and Guy M.
Tremblay for their helpful suggestions regarding the manuscript.
References
1 American Thoracic Society/European Respiratory Society.
Skeletal muscle dysfunction in chronic obstructive pulmonary
disease. Am J Respir Crit Care Med 1999; 159:S1–S40
2 Whittom F, Jobin J, Simard PM, et al. Histochemical and
morphological characteristics of the vastus lateralis muscle in
COPD patients: comparison with normal subjects and effects of
exercise training. Med Sci Sports Exerc 1998; 30:1467–1474
3 Bernard S, Leblanc P, Whittom F, et al. Peripheral muscle
weakness in patients with chronic obstructive pulmonary
disease. Am J Respir Crit Care Med 1998; 158:629 – 634
4 Hamilton AL, Killian KJ, Summers E, et al. Muscle strength,
symptom intensity and exercise capacity in patients with
cardiorespiratory disorders. Am J Respir Crit Care Med 1995;
152:2021–2031
5 Mostert R, Goris A, Weling-Scheepers C, et al. Tissue depletion
and health related quality of life in patients with chronic
obstructive pulmonary disease. Respir Med 2000; 94:859– 867
6 Marquis K, Debigaré R, LeBlanc P, et al. Mid-thigh muscle
cross-sectional area is a better predictor of mortality than
body mass index in patients with COPD. Am J Respir Crit
Care Med 2002; 166:809 – 813
7 Bernard S, Whittom F, Leblanc P, et al. Aerobic and strength
training in patients with COPD. Am J Respir Crit Care Med
1999; 159:896 –901
8 Schols AMWJ, Soeters PB, Mostert R, et al. Physiologic
effects of nutritional support and anabolic steroids in patients
with chronic obstructive pulmonary disease: a placebocontrolled randomized trial. Am J Respir Crit Care Med
1995; 152:1268 –1274
9 Turner HE, Wass JA. Gonadal function in men with chronic
illness. Clin Endocrinol (Oxf) 1997; 47:379 – 403
10 Kotler DP. Cachexia. Ann Intern Med 2000; 133:622– 634
11 Buck M, Chojkier M. Muscle wasting and dedifferentiation
induced by oxidative stress in a murine model of cachexia is
prevented by inhibitors of nitric oxide synthesis and antioxidants. EMBO J 1996; 15:1753–1765
12 Schols AMWJ, Buurman WA, Staal-van den Brekel AJ, et al.
Evidence for a relation between metabolic derangements and
increased levels of inflammatory mediators in a subgroup of
patients with chronic obstructive pulmonary disease. Thorax
1996; 51:819 – 824
13 Levine B, Kalman J, Mayer L, et al. Elevated circulating
levels of tumor necrosis factor in severe chronic heart failure.
N Engl J Med 1990; 323:236 –241
14 Ionescu AA, Nixon LS, Evans WD, et al. Bone density, body
composition, and inflammatory status in cystic fibrosis. Am J
Respir Crit Care Med 2000; 162:789 –794
15 Lamberts SW, van den Beld AW, van der Lely AJ. The
endocrinology of aging. Science 1997; 278:419 – 424
16 Kamischke A, Kemper DE, Castel MA, et al. Testosterone levels
in men with chronic obstructive pulmonary disease with or
without glucocorticoid therapy. Eur Respir J 1998; 11:41– 45
17 Casaburi R, Goren S, Bhasin S. Substantial prevalence of low
anabolic hormone levels in COPD patients undergoing rehabilitation [abstract]. Am J Respir Crit Care Med 1996; 153:A128
18 Anker SD, Clark AL, Kemp M, et al. Tumor necrosis factor and
steroid metabolism in chronic heart failure: possible relation to
muscle wasting. J Am Coll Cardiol 1997; 30:997–1001
19 Niebauer J, Pflaum CD, Clark AL, et al. Deficient insulin-like
growth factor I in chronic heart failure predicts altered body
composition, anabolic deficiency, cytokine and neurohormonal activation. J Am Coll Cardiol 1998; 32:393–397
20 Malm C, Nyberg P, Engstrom M, et al. Immunological
changes in human skeletal muscle and blood after eccentric
exercise and multiple biopsies. J Physiol 2000; 529:243–262
21 American Thoracic Society. Standards for the diagnosis and
care of patients with chronic obstructive pulmonary disease.
Am J Respir Crit Care Med 1995; 152:S77–S120
22 Knudson RJ, Slatin RC, Lebowitz MD, et al. The maximal
expiratory flow-volume curve: normal standards, variability
and effects of age. Am Rev Respir Dis 1976; 113:587– 600
23 Goldman HI, Becklake MR. Respiratory function tests: normal values at median altitudes and the prediction of normal
results. Am Rev Tuberc 1959; 79:454 – 467
24 Cotes JE, Hall AM. The transfer factors for the lung: normal
values in adults. In: Arcangeli P, ed. Normal values for
respiratory function in man. Torino, Italy: Panminerva Medica, 1970; 327–343
25 Tremblay RR, Massé J. Usefulness and limitation of bioavailable testosterone in assessment of androgenicity during the
process of aging male. Aging Male 1999; 2:16 –21
26 Van Snick J. Interleukin-6: an overview. Annu Rev Immunol
1990; 8:253–278
27 Ebisui C, Tsujinaka T, Morimoto T, et al. Interleukine-6
induces proteolysis by activating intracellular proteases
(cathepsins B and L, proteasome) in C2C12 myotubes. Clin
Sci (Lond) 1995; 89:431– 439
28 Mealy K, Robinson B, Millette CF, et al. The testicular
effects of tumor necrosis factor. Ann Surg 1990; 211:470 – 475
29 Ershler WB, Keller ET. Age-associated increased interleukin-6 gene expression, late-life diseases, and frailty. Annu Rev
Med 2000; 51:245–270
30 Ferrando AA, Tipton KD, Doyle D, et al. Testosterone
injection stimulates net protein synthesis but not tissue amino
acid transport. Am J Physiol 1998; 275:E864 –E871
31 Morales AJ, Haubrich RH, Hwang JY, et al. The effect of six
months treatment with a 100 mg daily dose of dehydroepiandrosterone (DHEA) on circulating sex steroids, body composition and muscle strength in age-advanced men and
women. Clin Endocrinol (Oxf) 1998; 49:421– 432
32 Tsuji K, Furutama D, Tagami M, et al. Specific binding and
effects of dehydroepiandrosterone sulfate (DHEA-S) on skeletal muscle cells: possible implication for DHEA-S replacement therapy in patients with myotonic dystrophy. Life Sci
1999; 65:17–26
33 Semple PD, Beastall GH, Watson WS, et al. Hypothalamicpituitary dysfunction in respiratory hypoxia. Thorax 1981;
36:605– 609
34 Gosney JR. Atrophy of Leydig cells in the testes of men with
longstanding chronic bronchitis and emphysema. Thorax
1987; 42:615– 619
35 Benbassat CA, Maki KC, Unterman TG. Circulating levels of
insulin-like growth factor (IGF) binding protein-1 and -3 in
aging men: relationships to insulin, glucose IGF, dand dehydroepiandrosterone sulfate and anthropometric measures.
J Clin Endocrinol Metab 1997; 82:1484 –1491
36 Benbassat CA, Lazarus DD, Cichy SB, et al. Interleukin-1
alpha (IL-1 alpha) and tumor necrosis factor alpha (TNF
alpha) regulate insulin-like growth factor binding protein-1
(IGFBP-1) levels and mRNA abundance in vivo and in vitro.
Horm Metab Res 1999; 31:209 –215
37 Anker SD, Chua TP, Ponikowski P, et al. Hormonal changes
and catabolic/anabolic imbalance in chronic heart failure and
their importance for cardiac cachexia. Circulation 1997;
96:526 –534
www.chestjournal.org
Downloaded From: http://publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21996/ on 06/15/2017
CHEST / 124 / 1 / JULY, 2003
89