International Journal of Cardiology 85 (2002) 141–149
C hronic heart failure and skeletal muscle catabolism:
effects of exercise training
Paul Christian Schulze, Stephan Gielen, Gerhard Schuler, Rainer Hambrecht
Universitat Leipzig, Herzzentrum GmbH, Klinik fur Innere Medizin/Kardiologie, Russenstr. 19, 04289 Leipzig, Germany
Although the clinical picture of cardiac cachexia is well-known in patients with advanced chronic heart failure (CHF) the factors that
determine who is at risk for this progressive catabolic syndrome and who is not remain unclear. Different endocrine systems have been
accused of being involved in this process: an imbalance between catabolic and anabolic steroids with an elevated cortisol/dihydroepian-
drosterone ratio, an increased resting metabolic rate due to high levels of circulating catecholamines, various cytokines are activated in
CHF (i.e. TNF-a, IL-6, IL-1b and others), and elevated levels of growth hormone (GH) with inappropriately normal or low serum levels
of insulin-like growth factor-I (IGF-I) have been described in cardiac cachexia. These catabolic factors contribute to peripheral muscle
atrophy, augment the expression of the inducible nitric oxide synthase (iNOS), which in turn inhibits the aerobic cellular metabolism. The
present review examines whether the catabolic factors can be influenced by a classical anabolic intervention: regular physical exercise
training. Long-term training programs increase skeletal muscle cytochrome c oxidase activity and are associated with reduced local
expression of pro-inflammatory cytokines as well as iNOS, and augment local IGF-I production. In concert, these beneficial effects of
exercise training may help to retard the catabolic process in CHF finally leading to cardiac cachexia and death.
2002 Elsevier Science Ireland Ltd. All rights reserved.
Keywords: Cachexia; Skeletal muscle alterations; iNOS expression; Insulin-like growth factor
1 . Introduction
tions lead to muscle disuse and consecutive loss of
If skeletal muscle atrophy were just a matter of
lack of exercise (i.e. disuse) it should be fully
reversed by an increase in exercise to normal or
above-normal levels. This is why systematic studies
of exercise training (as an established anti-catabolic
intervention) in CHF are so valuable for extending
our pathophysiological concept of exercise intoler-
The pivotal role of exercise intolerance and early
fatigue as the clinical hallmark of chronic heart
failure (CHF) has never been questioned since the
New York Heart Association (NYHA) adopted this
clinical feature for status determination in 1949 .
However, the debate whether to view skeletal muscle
weakness and atrophy as cause or consequence of
exercise intolerance has been continuing for decades:
is it primary skeletal muscle atrophy as part of the
heart failure syndrome that causes exercise intoler-
ance in CHF patients or do cardiac exercise limita-
2 . Catabolic factors in chronic heart failure
Although the final clinical picture of cardiac
cachexia is well-known in CHF patients with ad-
vanced heart failure, the factors that determine who is
*Corresponding author. Tel.: 149-341-865-1428; fax: 149-341-865-
E-mail address: firstname.lastname@example.org (R. Hambrecht).
0167-5273/02/$ – see front matter
2002 Elsevier Science Ireland Ltd. All rights reserved.
P.C. Schulze et al. / International Journal of Cardiology 85 (2002) 141–149
at risk for this progressive catabolic syndrome and
who is not remain unclear. Different endocrine
systems have been accused of being involved in this
process (Fig. 1).
increased levels of neuropeptide Y in the brain
consequently leading to anorexia in patients with
CHF . Unfortunately, no large-scale study has
systematically assessed the nutritional status of pa-
tients with CHF.
1. An imbalance between catabolic and anabolic
steroids with an elevated cortisol/dihydroepian-
drosterone ratio has been observed in CHF
2. An increased resting metabolic rate due to high
levels of circulating catecholamines has been
reported in CHF .
3. Various cytokines are activated in CHF (i.e.
TNF-a, IL-6, IL-1b and others) that have been
shown to contribute to loss of muscle bulk and
cachexia in CHF [4–6].
4. As a key regulator of normal growth, hyper-
trophy, and atrophy of tissues, the GH/IGF-I
axis has recently received more attention as a
potential factor for muscle catabolism and wast-
ing in CHF. Elevated levels of GH with in-
appropriately normal or decreased serum levels
of IGF-I have been described in cardiac cachex-
2 .1. Insulin-like growth factor I (IGF-I)
In animal models of catabolism the role of sys-
temic IGF-I levels has been closely investigated: in
rats with 30% body surface area burn injuries,
continuous infusion of IGF-I over 24 h was effective
in preventing the increased protein breakdown and
reduced protein synthesis in extensor digitorum lon-
gus muscles . This finding documents a potent
anticatabolic effect of systemic IGF-I.
In patients with CHF, Niebauer et al. observed an
association between low serum IGF-I levels and loss
of lean muscle mass as well as an increase in
catecholamines . This is consistent with the
hypothesis that decreases in systemic levels of IGF-I
occurs with advanced stages of heart failure. In a
recent study of skeletal muscle biopsies in non-
cachectic patients with CHF, the local IGF-I expres-
sion was substantially downregulated in the skeletal
muscle, despite normal IGF-I serum concentrations
This novel finding underlines that IGF-I can be
produced locally by skeletal muscle fibres and may
be regulated by factors independent from serum IGF-
I levels. Local skeletal muscle IGF-I expression
responds to stimuli from two different sources: (1)
serum GH has the potential to augment local IGF-I
expression. This mechanism is important for normal
growth and development of the organism. It has been
previously shown that a state of GH resistance may
develop in cardiac cachexia. (2) Skeletal muscle
IGF-I expression is modulated in response to altera-
tions in muscle use: in animal experiments it has been
shown that muscle unloading by zero gravity
(spaceflight for 16 days) resulted in growth retarda-
tion and decreased skeletal muscle IGF-I expression
in neonatal rats . While IGF-I overexpression
alone was ineffective in preventing hindlimb suspen-
sion-induced muscle atrophy  a combination of
GH/IGF-I supplementation and resistance exercise
preserved skeletal muscle mass and was effective in
preventing apoptosis in myonuclei and satellite cells
In addition to systemic and local abnormalities of
various endocrine systems, investigations into the
nutritional status of patients with CHF have shown
alterations of gastrointestinal fat absorption  al-
though intestinal protein loss does not seem important
. In addition, a central dysregulation of food intake
has been proposed since experimental data suggest
Fig. 1. Systemic and local regulatory mechanisms contributing to the
progressive catabolic syndrome in chronic heart failure.
P.C. Schulze et al. / International Journal of Cardiology 85 (2002) 141–149143
during unloading. This finding is consistent with the
hypothesis that both muscle loading/stretch and IGF-
I are required to avert atrophy. Of note, the frequency
with which apoptosis is seen in tissue samples of the
skeletal muscle is also increased in CHF . It is
therefore conceivable, that the apoptotic process in
the skeletal muscle might be accelerated in response
to a decline in local IGF-I expression.
Important interactions between TNF-a and IGF-I
have been discovered in animal models: TNF-a
decreased the IGF-I content of the liver and the
gastrocnemius muscle, whereas pretreatment with an
anti-TNF-a antibody completely prevented the de-
crease in IGF-I in the muscle .
severity of CHF . Serum IL-6 levels have been
found to correlate with plasma norepinephrine con-
centrations . It is thus conceivable that sympa-
thetic vasoconstriction triggers local IL-6 activation
at the endothelial or vascular smooth muscle level as
a compensatory mechanism inducing NO-dependent
2 .2.2. Direct metabolic effects
Inflammatory cytokines may influence the expres-
sion of functionally relevant muscle proteins. IL-1b
has been shown to downregulate the expression of
sarcoplasmic reticulum Ca
phospholamban at both mRNA and protein level in
neonatal myocytes . This causes a prolongation
of the calcium transient—an effect also initiated by
TNF-a [24,25]. Other factors like sphingosin have
also been proposed as potential mediators of the
negative inotropic actions of TNF-a on the myocar-
dium. TNF-a transgenic animal models have revealed
a number of additional pathways in the mouse
myocardium, e.g. increased activity of metallop-
roteinases, activation of both pro- and antiapoptotic
pathways, and a decrease in the a- and b-myosin
heavy chain mRNA ratio . All these molecular
changes converge in a reduced contractility.
ATPase (SERCA) and
2 .2. Cytokines, local inflammation, and iNOS
During the last decade immune activation and
inflammation in CHF has received growing attention
[4,17]. A number of proinflammatory factors have
evolved as potential mediators of inflammatory pro-
cesses in CHF: tumor necrosis factor a (TNF-a)
[18,19], interleukin 1b (IL-1b), interleukin 6 (IL-6),
and interferon g (IFN-g).
Cytokines may play a significant role for the
progression of CHF in three different contexts: they
are associated with poor prognosis and recurrent
hospitalizations, they exert direct metabolic effects on
the peripheral skeletal muscle, and they affect the
muscular energy metabolism via the inducible nitric
oxide synthase (iNOS) and intracellular accumulation
of toxic levels of NO.
2 .2.3. iNOS activation
As part of the inflammatory process initiated by
cytokine production, TNF-a, IFN-g, and IL-1b are
potent activators of iNOS expression , which is
known to be increased in the skeletal muscle of
patients with CHF . The intracellular accumula-
tion of NO generated by iNOS may produce toxic
levels of NO high enough to inhibit key enzymes of
the oxidative phosphorylation. In vitro experiments
documented that NO can thus attenuate the contrac-
tile performance of the skeletal muscle , a finding
which puts cytokine production and iNOS expression
in perspective for the development of exercise in-
tolerance in patients with severe heart failure.
2 .2.1. Prognostic implications
In a recent longitudinal study by Orus et al., 87
patients with advanced CHF (LV-EF 2466%) serum
cytokine levels and serum cytokine receptors were
included in a unvariate and a Cox analysis for
prognostic markers for a combined cardiac event
endpoint (death, new heart failure episodes, need for
heart transplantation ). By Cox regression serum
IL-6 was identified as independent predictor of
prognosis (P,0.0005) together with NYHA func-
tional class. By univariate analysis serum IL-1b,
TNF-soluble receptor I and II also predicted a cardiac
event. These findings are well in line with previous
data describing increasing IL-6 values with the
3 . Functional, metabolic, and morphologic
skeletal muscle alterations in CHF
Chronic heart failure has been found to be associ-
P.C. Schulze et al. / International Journal of Cardiology 85 (2002) 141–149
[30,31], and morphologic alterations in the skeletal
muscles [32,33]. In the course of these scientific
advances a new ‘muscle hypothesis of chronic heart
failure’  has been developed and peripheral
changes have become a new therapeutic target.
withprofound functional, metabolicgated in both animal models of CHF and in skeletal
muscle biopsies . In 47% of stable CHF patients,
TUNEL-positive nuclei were detected and confirmed
to lie in muscle fibres by counterstaining with anti-
actin antibodies . Evaluation of apoptosis positive
muscle specimens revealed an apoptotic index of
0.760.4%. The apoptotic frequency correlated with a
reduced exercise capacity (VO max).
In an animal model of monocrotaline-induced right
ventricular heart failure, Vescovo et al. demonstrated
that the number of TUNEL positive myonuclei in the
fast twitch muscle tibialis anterior increased sig-
nificantly over time compared to control rats (after 27
days; 0.002560.005% vs. 0.03160.012%). The in-
crease in apoptosis was accompanied by muscle
atrophy evident by a drop in fiber cross-sectional area
and muscle weight/body weight. Based on the avail-
able human and animal studies its seems that in CHF
apoptosis occurs in skeletal muscle, and that it may
have an influence on the muscle atrophy and contrac-
tility. The discussions on relevance and significance
of apoptosis in skeletal muscle are further compli-
cated by the fact that in each muscle fiber more than
100 nuclei are present, and that only a minority of
myonuclei inside the myofiber display DNA frag-
mentation (nuclear death) . Does the loss of a
single or of several nuclei alter fiber morphology or
even function? Based on the concept that one nucleus
controls a specific territory (nuclear domain), one has
to assume that the loss of a single nucleus is
associated with the loss of the controlled cytoplasmic
territory [43,44]. This hypothesis was confirmed by
Hikida et al. . They analyzed the myonuclear
population in the soleus muscle of rats that had
undergone atrophy due to 10 days spaceflight, and
could demonstrate that the number of nuclei was
reduced proportionally to the loss of fiber size.
3 .1. Functional and metabolic alterations in CHF
While exercise intolerance is generally considered
to be a clinical hallmark of CHF, systematic assess-
ments of skeletal muscle function in CHF are rela-
tively rare [11,29]. While maximal strength depends
on the number of contractile filaments, fatiguability is
influenced by intracellular ATP-stores and ATP
regeneration. We and others have previously shown
that oxidative phosphorylation is attenuated in CHF
patients, energy transfer by means of mitochondrial
creatine kinase is impaired, and overall ATP levels
are reduced [35,36]. These factors could explain why
muscle fatiguability develops earlier than reduction of
maximal contractile force which is a consequence of
To evaluate the metabolic responses to local
forearm or calf exercise in patients with chronic heart
failure, P magnetic resonance spectroscopy was
used. Despite normal limb blood flow during exer-
cise, patients exhibited abnormal phosphocreatine
depletion and acidosis during exercise [30,37].
In response to exercise, blood lactate levels in-
creased earlier than expected in CHF patients. Re-
duced oxidative enzymes, reduced mitochondrial
density, type I muscle fiber atrophy and an increase
in the proportion of type II fibers have all been
implicated as contributing factors for the increase of
anaerobic energy production in CHF [30,31,38–40].
As previously mentioned, the impairment of oxida-
tive phosphorylation may also be the consequence of
toxic intracellular levels of NO produced by iNOS.
4 . Effects of exercise training on skeletal muscle
3 .2. Skeletal muscle apoptosis
4 .1. Effects of training on aerobic metabolism
The ultimate result of catabolic processes in CHF
is skeletal muscle atrophy. On the microscopic level
atrophy is caused by an increased rate of programmed
cell death or apoptosis. The frequency and signifi-
cance of skeletal muscle apoptosis has been investi-
In a morphometric study we analysed the effects of
6 months of aerobic in-hospital and home-based
training on volume density of cytochrome c positive
mitochondria in skeletal muscle biopsies [46,47].
P.C. Schulze et al. / International Journal of Cardiology 85 (2002) 141–149145
(P,0.05) reduced. These findings indicate that a
substantial correction of the impaired oxidative
capacity of skeletal muscle in chronic heart failure
can be achieved by exercise training .
4 .2. Effects on cytokines, local inflammation, and
To date the effect of physical exercise on immune
activation in patients with CHF has never been
systematically addressed. Acute bouts of strenuous
exercise in healthy volunteers have been described to
induce an inflammatory response—especially under
circumstances of eccentric high-intensity training
with muscle trauma. Immediately after physical exer-
tion an increase in serum TNF-a and IL-1b has been
described —accompanied by a rise in several
antiinflammatory mediators like IL-1ra, sTNF-r1,
sTNF-r2, and IL-10. This inflammatory response to
acute bouts of strenuous physical exercise has also
been associated with influx of proinflammatory fac-
tors from the gut.
While acute physical exercise seems to mediate
pro-inflammatory effects, long-term endurance exer-
cise has been shown to act predominantly in an
immunosuppressive way: in a rat model of endurance
training Bagby et al. showed an attenuated TNF-a
release in response to bacterial lipopolysaccharide in
rats with prior exercise training . In line with this
animal experiment, Drenth et al. documented a
decrease of LPS-stimulated production of IL-1b and
TNF-a after a 5-km run in 19 well-trained athletes
. Taken together, these results show that pro-
longed exercise in healthy subjects elicits a selective
downregulation of the proinflammatory cytokine pro-
In a recent study we were able to show that local
expression of IL-1b and TNF-a in the quadriceps
muscle is reduced after long-term endurance training
of patients with CHF . This novel finding con-
firms that the anti-inflammatory effects of chronic
exercise previously described in healthy individuals
are also pertinent to patients with CHF. Reduction of
local cytokine expression was associated with a
reduced iNOS expression which may in turn contrib-
ute to a disinhibition of aerobic enzymes by reduction
of intracellular NO accumulation and protein nitro-
Fig. 2. Exercise training reverses the reduced volume density of COX-
positive mitochondria in the skeletal muscle of patients with chronic heart
failure (*P,0.05 vs. CHF baseline).
Initially surface and total volume density of cyto-
chrome c-oxidase-positive mitochondria was reduced
by |45% as compared to normal subjects, thereby
compromising oxidative capacity of working skeletal
muscle. Baseline volume density of cytochrome c
oxidase-positive mitochondria was closely related to
oxygen uptake at peak exercise. These changes in
oxidative capacity are at least partially reversible by
training therapy. The mean surface density of a single
cytochrome c oxidase-positive mitochondrium in-
creased by an average of 31% after exercise training,
whereas the total number of cytochrome oxidase-
changed. The significant increase in volume density
of cytochrome oxidase-positive mitochondria was
closely correlated with changes in oxygen uptake at
the ventilatory threshold and at peak exercise (Fig.
2). Moreover, exercise training leads to a ‘re-shift’
from fast-twitch type II fibers to slow-twitch type I
fibers in patients of the training group .
Using P nuclear magnetic resonance spectros-
copy Adamopoulos et al. measured phosphocreatine
depletion, muscle acidification and the increase in
ADP during the first 4 min of plantar flexion exercise
in the calf muscle of CHF patients, which were all
increased (P,0.04) as compared with values in
control subjects. After 8 weeks of training, phosphoc-
reatine depletion and the increase in ADP during
exercise were reduced significantly (P,0.003) and
phosphocreatine recovery half-time was significantly
P.C. Schulze et al. / International Journal of Cardiology 85 (2002) 141–149
4 .3. Effects of training on effects of exercise
training on skeletal muscle IGF-I expression
dual-energy X-ray absorptiometry (DEXA). In pa-
tients who increased their peak VO in response to
exercise training, body lean mass remained essential-
ly unchanged. The authors conclude that increases in
the oxidative capacity of the skeletal muscle and not
of muscle mass are responsible for the training effect.
Over the last decade, several prospective controlled
studies have addressed the question whether exercise
training improves the functional capacity of patients
with CHF. In a recent meta-analysis of randomised
controlled trials by the European Heart Failure
Training Group exercise training improved peak VO2
up to 2 ml/kg min . The clinical benefit
reported in terms of exercise tolerance is comparable
to the most effective pharmaceutical treatments: ACE
inhibitor therapy also increases peak VO
Of all non-humoral stimuli for IGF-I expression,
muscular stretch ranks among the most potent:
McKoy et al. recently confirmed that 4 days of
muscle stretch induced a significant upregulation of
IGF-mRNA  starting as early as 12 h after the
Exercise training as a natural form of stretch
exposure has similar effects on skeletal muscle IGF-I
expression. In a model of treadmill exercise in young
rats Eliakim et al. described a significant increase in
skeletal muscle IGF-I protein levels after 6 days with
no change in systemic IGF-I serum concentrations
In a recent study we observed a more than twofold
increase in local IGF-I expression after 6 months of
exercise training in patients with stable CHF. Two
other studies in non-CHF populations are available on
intramuscular changes of IGF-I expression in re-
sponse to exercise: one in military trainees docu-
mented a higher number of IGF-I immunoreactive
cells in skeletal muscle biopsies obtained after 1
week of terrain marching . A second assessed the
effect of a combined intervention of nutritional
supplementation and resistance training in 26 elderly
patients and confirmed a sixfold increase in local
IGF-I expression .
Our data are well in line with these previous
studies. For the first time it has been confirmed that
in CHF local IGF-I levels are reduced well before
any systemic changes are apparent. The local IGF-I-
deficient state associated with CHF responds to a
long-term aerobic training intervention indicating that
the catabolic state in the skeletal muscle is at least
partially reversible by adequate rehabilitation .
up to 2
4 .5. Training and skeletal muscle apoptosis
Despite the consensus that skeletal muscle apop-
tosis is present in biospies of patients with CHF and
in animal models of heart failure and may be relevant
for the development of skeletal muscle atrophy and
dysfunction, little is known about the effects of
physical exercise on the apoptotic rate.
In animal experiments, acute bouts of strenuous
physical exercise were associated with an increased
rate of apoptotic myonuclei . In healthy human
volunteers, however, it has been demonstrated that
cytosols from skeletal muscle biopsies lacked the
ability to activate type-2 caspases by a cytochrome
c-mediated pathway. This should represent a protec-
Unfortunately, the effect of long-term exercise
training has not been investigated so far neither in
healthy volunteers nor in CHF patients. One would
presume that the decrease of proapoptotic cytokines
and NO and the concomitant increase in IGF-I would
reduce the frequency of apoptosis. However, this has
not been confirmed so far.
4 .4. Effects of training on skeletal muscle mass
Although increase in muscle mass is the most
obvious result of training in healthy subjects only
limited information is yet available about the effect of
regular physical exercise on body composition or
muscle bulk in patients with heart failure. In an
observational study, Wilson et al.  investigated
the effect of training on body composition using
5 . Conclusion
In conclusion, intrinsic alterations in skeletal mus-
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