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Journal of the American College of Cardiology
© 2003 by the American College of Cardiology Foundation
Published by Elsevier Inc.
EDITORIAL COMMENT
Exercise Training and
Skeletal Muscle Inflammation
in Chronic Heart Failure:
Feeling Better About Fatigue*
Douglas L. Mann, MD, FACC,†‡
Michael B. Reid, PHD†
Houston, Texas
The classical definition of “heart failure” (HF) holds that
“heart failure occurs when an abnormality of cardiac function causes the heart to fail to pump blood at a rate required
by the metabolizing tissues or when the heart can do so only
with an elevated pressure” (1). However, the repeated
clinical observation that HF progresses independently of the
hemodynamic status of the patient has focused investigative
interest on the potential spectrum of mechanisms that are
responsible for disease progression in chronic HF. As a case
in point, attempts to correlate left ventricular function with
peak aerobic capacity and exercise capacity in chronic HF
patients have often been less than satisfying (2– 4). These
See pages 854 and 861
and other observations have led to a more detailed examination of the role of the peripheral circulation and the
skeletal musculature in HF. Thus far, the alterations in
skeletal muscle that have been described include muscle
atrophy, increased fiber type switching from oxidative type I
fibers to glycolytic type IIb fibers, decreases in myosin
heavy-chain type I fibers, decreases in mitochondrial enzymes involved in oxidation of fatty acids, as well as
decreases in cytochrome c oxidase and mitochondrial volume density (5,6). Importantly, many of the aforementioned
abnormalities cannot be explained solely by reductions in
regional limb blood flow, suggesting that there may be other
mechanisms that are responsible for producing these abnormalities.
In the current issue of the Journal, a pair of articles by
different investigative teams may shed new light on the
mechanisms that contribute to the chronic fatigue that is
emblematic of chronic HF. In the report by Gielen et al. (7),
20 male patients age 54 ⫾ 2 years with stable HF New York
*Editorials published in the Journal of the American College of Cardiology reflect the
views of the authors and do not necessarily represent the views of JACC or the
American College of Cardiology.
From the †Sections of Cardiology and Pulmonary Medicine, Winters Center for
Heart Failure Research, Department of Medicine, Baylor College of Medicine,
Houston, Texas; and the ‡Houston Veterans Administration Medical Center,
Houston, Texas. Supported by research funds from the Veterans Administration
(D.L.M.), National Institutes of Health (NIH) grants P50 HL-O6H and RO1
HL58081-01, RO1 HL61543-01, HL-42250-10/10 (D.L.M.), and NIH grants
HL45721 and HL59878 (M.B.R.)
Vol. 42, No. 5, 2003
ISSN 0735-1097/03/$30.00
doi:10.1016/S0735-1097(03)00847-7
Heart Association (NYHA) functional class II to III were
randomized to a training group (n ⫽ 10) or a control group
(n ⫽ 10). Exercise training was performed for six months
using bicycle ergometry at workloads that corresponded to
70% of the maximal oxygen uptake during symptom-limited
exercise. Peripheral levels of serum tumor necrosis factor
(TNF), interleukin (IL)-6, and IL-1␤ levels were measured
by enzyme-linked immunosorbent assay, and local cytokine
and inducible nitric oxide synthase (iNOS) messenger
ribonucleic acid (mRNA) expression were determined by
real-time quantitative polymerase chain reaction. Serum
samples and vastus lateralis muscle biopsies were obtained at
baseline and after six months. Consistent with previous
reports, Gielen et al. (7) observed that exercise training
improved peak oxygen uptake by approximately 30% in the
training group (p ⬍ 0.001 vs. control group). Whereas
serum levels of TNF, IL-6, and IL-1␤ remained unaffected
by training, levels of skeletal muscle mRNA for TNF,
IL-1␤, and IL-6 decreased significantly from baseline values
in the training group. Exercise training also reduced local
iNOS expression by 52% in the training group in agreement
with previous reports. Importantly, there was no change in
TNF, IL-1␤, IL-6, or iNOS mRNA levels in the control
group. As noted by the authors, one of the limitations of
their study was that the amount of skeletal muscle tissue
that was available by biopsy was too small to quantify
protein levels of TNF, IL-1␤, or IL-6. Thus, additional
studies will be required to confirm the role of exercise
training on the protein levels of inflammatory mediators in
the skeletal muscle of patients with HF.
In a second related article in this issue of the Journal,
Roveda et al. (8) studied the effects of exercise training in 16
patients (age 35 to 60 years) with NYHA class II to III HF.
Seven patients underwent exercise training, and nine patients served as sedentary controls. A normal control
exercise-trained group was also studied (n ⫽ 8). Exercise
training was performed for four months using bicycle
ergometry and local strengthening exercises, at heart rates
that corresponded up to 10% below the respiratory compensation point obtained during cardiopulmonary exercise
testing. Muscle sympathetic nerve activity was recorded
directly from the peroneal nerve using the technique of
microneurography. Consistent with previous reports, the
authors observed that baseline muscle sympathetic nerve
activity was greater in HF patients compared with normal
controls. The major new finding of this study was that
exercise training resulted in dramatic and uniform reductions in muscle sympathetic nerve activity in chronic HF
patients. Indeed, exercise training restored resting muscle
sympathetic nerve activity in the HF patients to levels that
were similar to those observed in trained normal controls.
Exercise training also resulted in an increase in peak oxygen
consumption and forearm blood flow, but not left ventricular ejection fraction, consistent with what has been reported in the literature. Taken together, these carefully done
870
Mann and Reid
Editorial Comment
studies provide further evidence that exercise training remains the most useful intervention that we have today to
correct the skeletal muscle alterations that occur in the
setting of chronic HF. However, above and beyond the
obvious implication of the findings of the studies by Gielen
et al. (7) and Roveda et al. (8), these studies may also
provide new insight into the mechanisms that are responsible for the chronic fatigue that plagues HF patients.
Inflammation, skeletal muscle mass, and fatigue. There
is increasing evidence that inflammatory mediators play an
important role in skeletal muscle wasting and fatigue in a
number of clinical settings, including HF (9 –11). Although
the exact mechanisms that are responsible for the expression
of proinflammatory cytokines in skeletal muscle are not
known, it is likely that oxidative stress is an important
upstream signal that activates the proinflammatory cascade.
As reviewed elsewhere (12), oxidative stress is sufficient to
activate nuclear factor-kappaB (NF-␬B), an important transcription factor for proinflammatory cytokine gene expression. Several potential triggers for oxidative stress in skeletal
muscle have already been identified, including strenuous
exercise and tissue injury, as well as repetitive stimulation of
skeletal muscle (13). Relevant to the report by Roveda et al.
(8) in this issue of the Journal, increased sympathetic tone in
skeletal muscle can lead to impaired local vasodilatory
responses in exercising muscle that may engender episodic
underperfusion and tissue ischemia and generation of reactive oxygen species (ROS).
The most obvious link between inflammatory mediators
and skeletal muscle wasting can be found in the systemic
sepsis literature, wherein inflammatory mediators have been
shown to lead to increased muscle catabolism (11). Among
the ensemble of inflammatory mediators that have been
implicated in sepsis, TNF (14) in particular has been shown
to provoke net nitrogen loss and catabolism of muscle
protein when administered to experimental animals (15,16).
Inflammatory cytokines can produce muscle wasting
through indirect (e.g., anorexia) as well as direct mechanisms. Recent studies have shown that TNF can directly
stimulate protein loss in differentiated muscle cells (17),
contradicting previous reports that the effects of TNF on
skeletal muscle were mediated entirely through indirect
mechanisms (18). Supporting a role for oxidants in this
process, Buck and Chojkier (19) have demonstrated that
either antioxidants or nitric oxide synthase (NOS) inhibitors
can inhibit muscle wasting and dedifferentiation in a mouse
model of TNF-induced cachexia. The effects of TNF in
skeletal myotubes appear to be mediated through an NF␬B-dependent increase in proteasomal degradation (20).
Indeed, acute intravenous injections of TNF result in
time-dependent increases in the levels of free and conjugated ubiquitin in skeletal muscle (21). Moreover, proteasome inhibitors suppress protein breakdown in rodent
muscle after experimental sepsis (22). Thus, these studies
suggest a role for the ubiquitin/proteasome pathway in
regulating the effects of sustained inflammation on skeletal
JACC Vol. 42, No. 5, 2003
September 3, 2003:869–72
muscle. Tumor necrosis factor can also promote muscle
catabolism by opposing the trophic effects of insulin on
skeletal muscle, although it is not clear whether this is
mediated directly at the level of the skeletal muscle cell or
indirectly through a rise in circulating catecholamine levels
(23).
Another potential link between inflammation and decreased skeletal muscle mass in HF is myocyte apoptosis.
Inflammatory mediators such as TNF can provoke apoptosis in skeletal myotubes (24). In experimental models of HF,
circulating levels of TNF are independently correlated with
the number of apoptotic myocyte nuclei in tibialis anterior
muscle (25). However, this effect appears to be more
prominent in fast-twitch than in slow-twitch muscle fibers
(26). Studies in patients with HF have yielded similar
findings. For example, apoptosis was detected in approximately 50% of patients with HF, whereas skeletal muscle
apoptosis was not detected in healthy subjects (27).
Patients with apoptosis-positive skeletal muscle myocytes
exhibited a significantly decreased maximal exercise capacity compared with patients with apoptosis-negative
biopsies (27,28). Similar findings were reported by
Vescovo et al. (28) who reported that peak oxygen
consumption was negatively correlated with the number
of terminal deoxynucleotidyltransferase-mediated UTPend labeling-positive nuclei and the skeletal muscle fiber
cross-sectional area in patients with HF.
Muscle weakness often can also occur in inflammatory
diseases without the overt loss of muscle protein (29,30).
Previous studies indicate that cytokines in general, and TNF
in particular, can lead to contractile dysfunction in striated
muscle (31,32). Although the full spectrum of mechanisms
that are responsible for inflammation-induced contractile
dysfunction in skeletal muscle are not known, recent studies
have suggested an important role for ROS. In a transgenic
mouse model that overexpresses TNF, we showed that there
was a profound weakening of diaphragm muscle force
generation that was accompanied by evidence of increased
cytosolic oxidative stress. Moreover, a reduced thiol donor
with antioxidant properties (N-acetylcysteine) reversed
much of the force deficit observed in the diaphragm muscle
of the TNF transgenic mice (33), suggesting that the
cytosolic oxidative stress was responsible for the contractile
dysfunction in this study.
As described in a recent review (13), ROS have biphasic
effects on the contractile function of unfatigued skeletal
muscle. The low ROS levels that are present in muscle fibers
under basal conditions are essential for normal force production, whereas higher ROS concentrations lead to a
decrease in force generation. These negative effects can be
inhibited by pretreating muscles with antioxidants or can be
reversed by post hoc administration of reducing agents.
Interestingly, the rise in ROS production that occurs during
strenuous exercise contributes to the development of acute
muscle fatigue. In this setting, muscle-derived ROS are
generated faster than they can be buffered by endogenous
Mann and Reid
Editorial Comment
JACC Vol. 42, No. 5, 2003
September 3, 2003:869–72
antioxidants. As ROS accumulate in the working muscle,
they inhibit force production (34). Indeed, there is increasing evidence that oxidative stress plays an important role as
a mechanism for the muscle fatigue that occurs in aging,
sepsis, and malignant hyperthermia. Moreover, there is
experimental evidence that oxidative stress may play a role in
the muscle fatigue that occurs in HF. In a model of acute
coronary artery ligation, Tsutsui et al. (35) used electron
spin resonance spectroscopy to demonstrate increased ROS
in soleus and gastrocnemius muscles. In addition to causing
muscle weakness via oxidative stress, inflammatory mediators can also lead to muscle weakness through nitrosative
stress. Skeletal muscle constitutively expresses NOS and
continually produces reactive nitrogen species at low rates
(36). Inflammatory mediators such as TNF can increase the
production of reactive nitrogen species by muscle fibers,
which elevates intracellular oxidant levels, decreases force
production (37), and, in the extreme, can cause cellular
injury or death.
Conclusion. Taken together, the foregoing observations
suggest the interesting possibility that inflammatory mediators contribute to the skeletal muscle fatigue that plagues
patients with HF, both through a decrease in muscle mass,
as well as through an increase in the levels of ROS that
negatively modulate skeletal muscle force generation. Accordingly, the findings by Gielen et al. (7) that exercise
training reduces skeletal muscle inflammation may have
significant clinical importance. This statement notwithstanding, it must be emphasized that the study by Gielen et
al. (7) is descriptive and does not definitively prove a causal
link between skeletal muscle inflammation and increased
muscle weakness and fatigue. Thus, these studies must be
viewed as provisional at present.
Nonetheless, when the observations by Gielen et al. (7)
are coupled with the observation that exercise training
increases the expression of anti-oxidative enzyme genes in
the skeletal muscle of HF patients (38), the aggregate data
suggest that one of the beneficial aspects of exercise training
may be to increase the capacity of skeletal muscle to buffer
increased ROS that are generated during routine exercise.
The increased capacity to buffer exercise-induced ROS
would translate into decreased ROS, decreased inflammation, decreased skeletal muscle catabolism, and increased
skeletal muscle force generation. Moreover, the exercise
training–induced decrease in skeletal muscle sympathetic
nerve activity reported by Roveda et al. (8) suggests that
exercise training may reduce skeletal muscle inflammation
by decreasing regional vasoconstriction, increasing regional
blood flow, and reducing episodic bouts of exercise-induced
ischemia and tissue hypoxia, both of which would be
expected to generate ROS. Finally, the carefully done
studies by Gielen et al. (7) and Roveda et al. (8) in this issue
of the Journal illustrate the tremendous opportunity that
exercise training provides in terms of learning more about
the basic mechanisms that contribute to the syndrome of
HF. That is, analogous to the situation with left ventricular
871
assist devices, wherein investigators have the opportunity to
study structure and function relationships in myocardial
tissue after hemodynamic unloading of the heart, exercise
training also provides a unique opportunity to study structure and function relationships in skeletal muscle before and
after an intervention that is clearly beneficial. And indeed,
these are the types of questions that investigators now
have the opportunity to address in the ongoing National
Institutes of Health sponsored trial HF-ACTION (Heart
Failure—A Controlled Trial Investigating Outcomes of
exercise traiNing) (6), which has just started recruitment in
North America.
Reprint requests and correspondence: Dr. Douglas L. Mann,
Winters Center for Heart Failure Research, MS 524, 6565
Fannin, Houston, Texas 77030. E-mail: [email protected].
REFERENCES
1. Heart Failure: Evaluation and Care of Patients With Left-Ventricular
Systolic Dysfunction. Bethesda, MD: U.S. Department of Health and
Human Services, 1994. Clinical Practice Guideline No. 11.
2. Szlachcic J, Massie BM, Kramer BL, Topic N, Tubau J. Correlates
and prognostic implication of exercise capacity in chronic congestive
heart failure. Am J Cardiol 1985;55:1037–42.
3. Higginbotham MB, Morris KG, Conn EH, Coleman RE, Cobb FR.
Determinants of variable exercise performance among patients with
severe left ventricular dysfunction. Am J Cardiol 1983;51:52–60.
4. Franciosa JA, Park M, Levine TB. Lack of correlation between
exercise capacity and indexes of resting left ventricular performance in
heart failure. Am J Cardiol 1981;47:33–9.
5. Drexler H, Riede U, Munzel T, Konig H, Funke E, Just H.
Alterations of skeletal muscle in chronic heart failure. Circulation
1992;85:1751–9.
6. Pina IL, Apstein CS, Balady GJ, et al. Exercise and heart failure: a
statement from the American Heart Association Committee on
exercise, rehabilitation, and prevention. Circulation 2003;107:1210 –
25.
7. Gielen S, Adams V, Möbius-Winkler S, et al. Anti-inflammatory
effects of exercise training in the skeletal muscle of patients with
chronic heart failure. J Am Coll Cardiol 2003;42:861– 8.
8. Roveda F, Middlekauff HR, Rondon MUPB, et al. The effects of
exercise training on sympathetic neural activation in advanced heart
failure: a randomized controlled trial. J Am Coll Cardiol 2003;42:854 –
60.
9. Farber MO, Mannix ET. Tissue wasting in patients with chronic
obstructive pulmonary disease. Neurol Clin 2000;18:245–62.
10. Anker SD, Rauchhaus M. Insights into the pathogenesis of chronic
heart failure: immune activation and cachexia. Curr Opin Cardiol
1999;14:211–6.
11. Moldawer LL, Sattler FR. Human immunodeficiency virus-associated
wasting and mechanisms of cachexia associated with inflammation.
Semin Oncol 1998;25:73–81.
12. Baeuerle PA, Baltimore D. NF-kB: ten years after. Cell 1996;87:13–
20.
13. Reid MB. Invited review: redox modulation of skeletal muscle contraction: what we know and what we don’t. J Appl Physiol 2001;90:
724 –31.
14. Espat NJ, Copeland EM, Moldawer LL. Tumor necrosis factor and
cachexia: a current perspective. Surg Oncol 1994;3:255–62.
15. Oliff A, Defeo-Jones D, Boyer M, et al. Tumors secreting human
TNF/Cachectin induce cachexia in mice. Cell 1987;50:555–63.
16. Tracey KJ, Wei H, Manogue KR, et al. Cachectin/tumor necrosis
factor induces cachexia, anemia, and inflammation. J Exp Med
1988;167:1211–27.
17. Li YP, Schwartz RJ, Waddell ID, Holloway BR, Reid MB. Skeletal
muscle myocytes undergo protein loss and reactive oxygen-mediated
NF-kappaB activation in response to tumor necrosis factor alpha.
FASEB J 1998;12:871–80.
872
Mann and Reid
Editorial Comment
18. Garcia-Martinez C, Lopez-Soriano FJ, Argiles JM. Acute treatment
with tumour necrosis factor-alpha induces changes in protein metabolism in rat skeletal muscle. Mol Cell Biochem 1993;125:11–8.
19. 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;
15:1753–65.
20. Li YP, Reid MB. NF-kappaB mediates the protein loss induced by
TNF-alpha in differentiated skeletal muscle myotubes. Am J Physiol
Regul Integr Comp Physiol 2000;279:R1165–70.
21. Garcia-Martinez C, Agell N, Llovera M, Lopez-Soriano FJ, Argiles
JM. Tumour necrosis factor-␣ increases the ubiquitinization of rat
skeletal muscle proteins. FEBS Lett 1993;323:211–4.
22. Hochstrasser M. Ubiquitin, proteasomes, and the regulation of intracellular protein degradation. Curr Opin Cell Biol 1995;7:215–23.
23. Patiag D, Gray S, Idris I, Donnelly R. Effects of tumour necrosis
factor-alpha and inhibition of protein kinase C on glucose uptake in
L6 myoblasts. Clin Sci (Lond) 2000;99:303–7.
24. Meadows KA, Holly JM, Stewart CE. Tumor necrosis factor-alphainduced apoptosis is associated with suppression of insulin-like growth
factor binding protein-5 secretion in differentiating murine skeletal
myoblasts. J Cell Physiol 2000;183:330 –7.
25. Dalla Libera L, Sabbadini R, Renken C, et al. Apoptosis in the skeletal
muscle of rats with heart failure is associated with increased serum
levels of TNF-alpha and sphingosine. J Mol Cell Cardiol 2001;33:
1871–8.
26. Libera LD, Zennaro R, Sandri M, Ambrosio GB, Vescovo G.
Apoptosis and atrophy in rat slow skeletal muscles in chronic heart
failure. Am J Physiol 1999;277:C982–6.
27. Adams V, Jiang H, Yu J, et al. Apoptosis in skeletal myocytes of
patients with chronic heart failure is associated with exercise intolerance. J Am Coll Cardiol 1999;33:959 –65.
JACC Vol. 42, No. 5, 2003
September 3, 2003:869–72
28. Vescovo G, Volterrani M, Zennaro R, et al. Apoptosis in the skeletal
muscle of patients with heart failure: investigation of clinical and
biochemical changes. Heart 2000;84:431–7.
29. Budgett R. Fatigue and underperformance in athletes: the overtraining
syndrome. Br J Sports Med 1998;32:107–10.
30. Simon AM, Zittoun R. Fatigue in cancer patients. Curr Opin Oncol
1999;11:244 –9.
31. Wilcox P, Osborne S, Bressler B. Monocyte inflammatory mediators
impair in vitro hamster diaphragm contractility. Am Rev Respir Dis
1992;146:462–6.
32. Wilcox PG, Wakai Y, Walley KR, Cooper DJ, Road J. Tumor
necrosis factor alpha decreases in vivo diaphragm contractility in dogs.
Am J Respir Crit Care Med 1994;150:1368 –73.
33. Li X, Moody MR, Engel D, et al. Cardiac-specific overexpression
of tumor necrosis factor-alpha causes oxidative stress and contractile dysfunction in mouse diaphragm. Circulation 2000;102:
1690 –6.
34. Reid MB, Li YP. Cytokines and oxidative signalling in skeletal muscle.
Acta Physiol Scand 2001;171:225–32.
35. Tsutsui H, Ide T, Hayashidani S, et al. Enhanced generation of
reactive oxygen species in the limb skeletal muscles from a murine
infarct model of heart failure. Circulation 2001;104:134 –6.
36. Reid MB, Kobzik L, Bredt DS, Stamler JS. Nitric oxide modulates
excitation-contraction coupling in the diaphragm. Comp Biochem
Physiol A Mol Integr Physiol 1998;119:211–8.
37. Murrant CL, Andrade FH, Reid MB. Exogenous reactive oxygen and
nitric oxide alter intracellular oxidant status of skeletal muscle fibres.
Acta Physiol Scand 1999;166:111–21.
38. Ennezat PV, Malendowicz SL, Testa M, et al. Physical training
in patients with chronic heart failure enhances the expression of
genes encoding antioxidative enzymes. J Am Coll Cardiol 2001;38:
194 –8.