[Frontiers in Bioscience 13, 302-311, January 1, 2008]

Impact of physical exercise on alterations in the skeletal muscle in patients with chronic
heart failure

Volker Adams, Christian Doring, Gerhard Schuler

University Leipzig, Heart Center Leipzig, Leipzig, Germany

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. Impact of exercise training on muscle fiber type distribution and muscle fiber size
4. Impact of exercise training on inflammatory cytokine expression
5. Impact of exercise training on anabolic / catabolic balance: Ubiquitin proteasome system,
apoptosis versus IGF-1
5.1. Ubiquitin Proteasome system
5.2. Apoptosis
5.3. Insulin-like growth factor-1
6. Impact of exercise training on oxidative stress
7. Impact of exercise training on metabolism and mitochondrial oxidative phosphorylation
8. Impact of exercise training on capillary density in skeletal muscle
9. Perspective
7. References

1. ABSTRACT

Chronic heart failure (CHF) is a condition characterized by exercise intolerance. The level of activity
tolerated by an individual cannot be predicted by classical parameters of left ventricular
performance. Therefore, considerable attention has been focused on the role of peripheral factors
such as skeletal muscle, which are determinants of work capacity. In recent years, many alterations
in the skeletal muscle have been described in patients with chronic heart failure. This knowledge
has dramatically changed the treatment of patients with CHF. Previously, patients were asked to
avoid excessive strain and physical exercise. Recently, however, patients are asked to participate
in a supervised physical training program to increase their exercise capacity and to counteract the
molecular changes occurring in the skeletal muscle. This review will focus on molecular and
biochemical alterations especially in the skeletal muscle and how these alterations are influenced
by exercise training finally contributing to better skeletal muscle performance.

2. INTRODUCTION

An estimated 5 million Americans have been diagnosed with heart failure (HF), a chronic condition
associated with frequent hospitalization, widespread functional limitations, and a high mortality rate.
Each year, approximately 550,000 new cases are detected and nearly 300,000 patients die of heart
failure as a primary or contributory cause. Since HF is not a homogenous disease the management
of these patients is extremely challenging. Primary goals of HF management include reduction in
the frequency of HF as well as extending and improving quality of life. Additional goals are
maximizing independence, and improving exercise capacity. To treat HF numerous
pharmacological agents have been developed to improve central hemodynamics and myocardial
contractility. Nevertheless, after initiation of such therapies patients still continue to experience
activity-related symptoms like, shortness of breath, muscle fatigue and weakness. It is well known
that measures of cardiac function like left ventricular ejection fraction correlate poorly with the
clinical severity of heart failure (1,2). Therefore, exercise has become an integral component of the
management of patients with chronic heart failure. The main goal of exercise training is to improve
physical activity and to counteract exercise intolerance, which is one of the hallmarks of the
disease. Over the last ten years many different investigators could document the beneficial effect of
exercise training in HF patients. In addition, molecular biology helped us to understand the
molecular and biochemical basis for the observed effects.

3. IMPACT OF EXERCISE TRAINING ON MUSCLE FIBER TYPE DISTRIBUTION AND MUSCLE

FIBER SIZE

Skeletal muscle abnormalities represent an inherent feature of patients with CHF. These include a
shift in fiber type distribution with a transformation of slow-twitch type I to fast-type II fibers (for
review see 3). Fast-twitch fibers (type II) have a low aerobic capacity and are easily fatigued.
Beside the alterations in muscle fiber type distribution, the development of CHF is also associated
with a decreased size (muscle cross-sectional area) in both type I and type II fibers.

Has any form of exercise training an influence on the fiber type distribution and muscle cross
sectional area in patients with CHF? The analysis of data recently published revealed that the
results are conflicting. Investigating the impact of 6 month ergometer training at 70% of maximal
oxygen uptake (VO2max) in patients with CHF (n=18), Hambrecht and colleagues reported for the
first time a significant 8% increase in type I fibers, whereas type II fibers decreased significantly (4).
During this time period a 6% decrease in the amount of type I fibers was observed in the control
group. Fiber size was not investigated in this study. In a study published 3 years later, Kiilavuori
and coworkers were not able to confirm the change in fiber type distribution after 6 month of
moderate exercise training (5). In addition, no change in fiber size was documented. Looking
specifically at female related skeletal muscle change, Tyni-Lenne showed that 8 weeks of intensive
knee extensor endurance training increased the cross-sectional area of muscle fibers which after
the exercise training was no longer distinguishable from healthy controls (6). What is the difference
between the studies and why do we obtain so inhomogeneous results? So far the answer can only
be speculative. All the studies differ in training intensity and time. At least, it seems that high
intensity training is necessary to benefit from the training program with respect to fiber type
distribution and muscle cross-sectional area.

What are possible molecular mechanisms responsible for the fiber type shift during the
development of CHF and after exercise training? One molecular candidate influencing the fiber
type composition of a skeletal muscle may be the peroxisome proliferator-activated receptor
gamma coactivator-1alpha (PGC-1alpha). It is well known, that PGC-1alpha is down regulated in
CHF (7,8), that it is involved in muscle fiber type switching during development (9) and that it is
induced in skeletal muscle after exercise training (10). The importance of PGC-1alpha as
modulator for fiber type composition is furthermore supported by correlation analysis between the
skeletal muscle fiber type and the PGC-1alpha expression (11) as well as by studies using
transgenic animals (9).

4. IMPACT OF EXERCISE TRAINING ON INFLAMMATORY CYTOKINE EXPRESSION

Both systemic and local inflammation has been suggested to play an important role in the
pathogenesis and progression of CHF (12). Cytokines may affect muscle metabolism and strength
by direct effects, for example, by altering the expression of the sarcoplasmic reticulum Ca 2+-
ATPase and phospholamban (13), or by induction of other pathological factors, most notably
inducible nitric oxide synthase (iNOS) (14,15). A detailed analysis of the serum from asymptomatic
patients enrolled into the SOLVD study (16), or patients with severe HF (17), revealed a stringent
correlation between the serum concentration of tumor necrosis factor alpha (TNF-alpha) and the
severity of the disease. Moreover, circulating levels of cytokines and cytokine receptors have
acquired prognostic significance (18-20). Several studies have been performed in the recent years
to investigate the impact of physical exercise training on the concentrations of circulating
inflammatory cytokines. Depending on the disease severity of the enrolled patients and the training
intensity the results differ significantly. For example, Adamopoulos and colleagues described that
12 weeks of exercise training (five days per week at 60-80% of maximum heart rate) of patients in
New York Heart Association class II/III (NYHA II/III) reduced plasma levels of proinflammatory
cytokines like TNF-alpha, its soluble receptors and interleukin-6 (21). In addition, a good correlation
was found between a training-induced increase in VO2max and the training-induced reduction in
levels of TNF-alpha (21). On the other hand, several other studies applying comparable training
modalities were not able to confirm these anti-inflammatory effects of exercise training (22-24).

Based on these observations, the question was raised, if the concentration of inflammatory
cytokines measured in the plasma is not only a sign of a high local concentrations of the
inflammatory factors. This notion is supported by the observation of Sagizadeh, who first described
the expression of TNF-alpha in skeletal muscle myocytes (25). This could be confirmed several
years later by our group (23). Instead of investigating changes in the plasma concentration of
inflammatory cytokines, Gielen and coworkers analyzed for the first time the impact of physical
exercise training on the local cytokine expression (23). Despite no changes observed in plasma
concentration, a significant down-regulation of inflammatory cytokine expression in the myocytes
was noted. This clearly demonstrates, that the local alteration in cytokine expression is influenced
much earlier before changes are evident in the circulating system.

5. IMPACT OF EXERCISE TRAINING ON THE ANABOLIC CATABOLIC BALANCE:

UBIQUITIN-PROTEASOME SYSTEM, APOPTOSIS VERSUS IGF-1

A general loss of skeletal muscle mass (muscle atrophy) is a characteristic, debilitating response to
fasting, as well as many severe diseases, including advanced cancer, renal failure, sepsis, and
chronic heart failure (26-29). In most types of muscle atrophy overall rates of protein synthesis are
suppressed and rates of protein degradation are consistently elevated. This response accounts for
the majority of the rapid loss of muscle protein. These processes are paralleled by the activation of
apoptosis, the cell suicide program, which leads to a progressive loss of muscle myocyte nuclei,
further contributing to the development of muscle atrophy.

5.1. Ubiquitin Proteasome system

In a variety of animal models for different human diseases (e.g., fasting (30,31), diabetes (32),
cancer cachexia (33-35), acidosis (36), sepsis (37), disuse atrophy (38), denervation (30), and
glucocorticoid treatment (39)), most of the accelerated proteolysis in muscle appears to be due to
an activation of the Ubiquitin-proteasome system (UPS) (40). The UPS is an ATP requiring multi-
enzymatic process. Proteins degraded by the UPS are first conjugated to ubiquitin. This reaction
requires the activation of ubiquitin by the ubiquitin-activating enzyme (E1), transfer to an ubiquitin
conjugating enzyme (E2), and subsequent linkage to the lysine residue of proteins destined for
degradation (E3) (41). Expression of the E3-ligases Murf-1 (for Muscle Ring Finger 1) and
atrogin1/MAFbx (for Muscle Atrophy F-box) (42) is restricted to heart and skeletal muscle tissue.
Murf-1 shows ubiquitin ligases activity (43), binds the sarcomeric protein titin (44), and degrades
cardiac troponin I (43). MAFbx interacts with calcineurin A, alpha-actinin-2 (45), and degrades
MyoD (46), respectively. At least in skeletal muscle cells TNF-alpha is able to stimulate the
expression of MAFbx via the activation of p38MAPK (47). Do we have some evidence from the
current literature, that exercise training influences the ubiquitin-proteasome-pathway? At least from
animal experiments using healthy rats we know, that endurance exercise training over a period of 5
days significantly reduced the UPS activity (48). Concerning the impact of exercise training on the
UPS in patients with heart failure the evidence is low. Preliminary data from our group
demonstrated that 4 weeks aerobic training of patients with chronic heart failure was efficient in
reducing the elevated Murf-1 expression (49).

5.2. Apoptosis

Apoptosis is a highly regulated form of cell death that is characterized by specific morphological,
biochemical, and molecular events (50). It is essential for the normal development of a multi-
cellular organism (51) and apoptosis is involved in cell turnover in healthy adult tissues (52).
Studies in humans as well as in several animal models over the last years showed, that the
development of heart failure is associated with an increase in apoptotic myonuclei. Furthermore,
the degree of apoptosis correlated with the severity of the disease. This has been shown to be true
in experimental models of CHF (53-55) and in humans with CHF (56,57). In rats treated with
monocrotaline the degree of skeletal muscle apoptosis correlated directly with the degree of right-
ventricle dilatation, while in humans apoptosis correlated inversely with peak oxygen consumption.
Concerning the impact of an exercise training intervention on apoptosis no data are available so far
from patients with chronic heart failure, as well as from CHF animal models.

5.3. Insulin-like growth factor-1

Insulin-like growth factor 1 (IGF-1) is another important factor regulating skeletal muscle mass. A
significant portion of IGF-1 is produced locally by skeletal muscle myocytes and acts as a paracrine
regulator of skeletal muscle hypertrophy/atrophy. Several human and animal studies in the current
literature demonstrated that chronic heart failure is associated with a reduced expression of IGF-1
in the skeletal muscle when compared to healthy controls (58,59). The plasma concentration was
not altered under these conditions. The local IGF-1 expression correlated significantly with muscle
cross sectional area, indicating that the local IGF-1 deficiency might contribute to loss of muscle
bulk in CHF (58). Previous studies have shown that the local expression of IGF-1 in skeletal muscle
is mainly regulated by two different mechanisms. (1) Growth hormone (GH) induces the local
expression of IGF-1 through the activation of the GH-receptor (60) and (2) inflammatory cytokines
like TNF-alpha decreases the IGF-1 expression (61,62) by interfering with the transcription factor
CREB (cAMP responsive element binding protein), which regulates the transcription of IGF-1 (63).
Based on the fact, that exercise training influences the expression of inflammatory cytokines (see
above), it is reasonable to assume that exercise training has also an effect on the expression of
IGF-1. In a study by Schulze and coworkers a more than two-fold increase in local IGF-1
expression after 6 months of exercise training in patients with stable CHF was observed (64). Two
other studies also investigated in non-CHF populations the intramuscular changes of IGF-1
expression in response to exercise. One study documented a higher number of IGF-1
immunoreactive cells in skeletal muscle biopsies obtained after 1 week of terrain marching (65). A
second study assessed the effect of a combined intervention - nutritional supplementation and
resistance training - on muscular IGF-1 expression (66). The authors reported a six-fold increase in
local IGF-1 expression after 10 weeks (66). Therefore, it seems that the local IGF-I-deficiency
responded to long-term aerobic exercise indicating that the catabolic state in the skeletal muscle is
at least partially reversible by adequate exercise training.

6. IMPACT OF EXERCISE TRAINING ON OXIDATIVE STRESS

In patients with CHF and animal models of HF excessive oxidative stress in skeletal muscle has
been linked to peripheral hypo-perfusion as a consequence of low cardiac output and peripheral
endothelial dysfunction (67-70). Various neurohormonal factors, including catecholamines,
angiotensin II, and cytokines, all known to be increased in heart failure, can activate the generation
of reactive oxygen species (ROS) by activating ROS producing enzyme like xanthine oxidase or
altering mitochondrial function (for review see 71). A cross-talk between oxidative stress and local
inflammation has to be postulated. ROS are known to induce the expression of inflammatory
cytokines (72), and it is also described that cytokines themselves promote the production of ROS
(15,72). The concentration of ROS in the tissue has to be tightly controlled since it contributes to
loss of muscle bulk. For this purpose the skeletal muscle, as all other tissues, is equipped with a
variety of anti-oxidative enzymes like copper-zinc superoxide dismutase (CuZnSOD), manganese
superoxide dismutase (MnSOD), glutathione peroxidase (GPX), and catalase (Cat) to protect the
cells from ROS attacks (73).

Has exercise training any influence on the oxidant-antioxidant homeostasis in the skeletal muscle?
To address this question we have to discriminate between single exercise bouts and an exercise
program over a longer period of time. It is very well documented in the current literature that heavy
exercise is associated with a dramatic increase in oxygen uptake particularly by the skeletal
muscle. Using electron spin resonance spectroscopy (ESR), Davies et al (74) demonstrated that
free radical signals were intensified in rat hind limb muscle after an acute bout of treadmill running
to exhaustion. No data are available so far analyzing the impact of endurance training on ROS
production by using ESR. Looking at the antioxidant system more data are available with regard to
exercise training. At least four different studies, two animal studies (75,76) and two human studies
(77,78), indicate that exercise training induces the expression of anti-oxidative enzymes in the
skeletal muscle by 40 to 100%. This observation is not limited to CHF. Also in healthy animals,
exercise training increases protective stress proteins in skeletal muscle including anti-oxidative
enzymes and heat shock proteins (79,80).

The concept that exercise training in CHF patients exerts long-term anti-oxidative effects is further
supported by the convincing normalization of lipid peroxidation and a reduction in nitrotyrosine
formation, as measures of local oxidative stress, seen in the skeletal muscle of CHF patients after 6
months of exercise training (78). This attenuation in local oxidative stress was closely associated
with a decrease in the rate of skeletal muscle apoptosis in CHF (78).

7. IMPACT OF EXERCISE TRAINING ON METABOLISM AND MITOCHONDRIAL OXIDATIVE

PHOSPHORYLATION

As a matter of fact, large metabolic defects are central features of the skeletal muscle from CHF
patients and animal models of the syndrome. In several studies a rapid phosphocreatine (PCr)
depletion, an increase in lactate production during exercise and a delayed PCr-recovery at the end
of exercise could be documented (81,82). Skeletal muscles of CHF patients usually show an
increased activity of glycolytic enzymes, whereas mitochondrial volume and enzymes of oxidative
phosphorylation are significantly decreased (3,83). A fundamental enzyme system for energy
production and transfer in the skeletal muscle is the PCr system. In a few studies it could be
documented that the MM-isoform of creatine kinase (CK), as well as the mitochondrial isoform of
the enzyme (mi-CK), is affected in the skeletal muscle of patients with CHF. These CK isoenzyme
alterations could change the function of mitochondria including energy production as well as the
sarcoplasmic reticulum. This will lead to a mismatch between energy production and utilization.
Therefore, the decreased oxidative capacity of the skeletal muscle and the altered mitochondrial
regulation and energy transfer may be a mechanistic link for the decreased oxygen utilization and
exercise capacity, which are hallmarks in CHF.

Already in 1985, Howald and colleagues investigated the impact of endurance exercise on the
ultrastructural morphology of skeletal muscle mitochondria (84). They could show, that endurance
training promotes an increase in volume density of the mitochondria and an increase in
mitochondrial protein expression. With the possibility to measure the function of the total
mitochondrial population in situ using freshly saponin skinned muscle fibers it became evident that
in an animal model exercise training over a period of 8 weeks (cages equipped with a running
wheel) nearly fully restored metabolic parameters as well as oxidative capacity, mitochondrial
enzymes and components of the phosphocreatine system (85). An explanation for the beneficial
effect of exercise training on the CK system might be the anti-inflammatory effect of exercise
training leading to a decreased expression of the inducible nitric oxide synthase (iNOS) (23), which
demonstrates an inverse relationship with the mi-CK isoform (86). Beside nitric oxide, PGC-1alpha
is another factor that may influence muscle oxidative capacity . PGC-1alpha plays a key role in
regulating mitochondrial biogenesis in the skeletal muscle (for review see 87,88). The expression of
PGC-1alpha is downregulated in experimental HF (7) and patients with CHF (8). Concerning the
impact of exercise training of humans on the expression of PGC-1alpha only few data are
available. Analyzing the impact of exercise training in healthy subjects Kuhl and colleagues
detected after 12 weeks of a combined aerobic and strength training a significant increase in PGC-
1alpha protein expression (89). Performing a low-intensity concentric and eccentric endurance-type
training program in patients with coronary artery disease over a period of 8 weeks no alterations in
PGC-1alpha were evident (90). The reason for this discrepancy in outcome is speculative at the
moment, but one explanation may be exercise intensity. So far no results are available for patients
with CHF enrolled into a training program.

8. IMPACT OF EXERCISE TRAINING ON CAPILLARY DENSITY IN SKELETAL MUSCLE

The vascular bed in skeletal muscle functions to supply oxygen and to remove waste products from
skeletal muscle fibers. Therefore, the relative capillary density of a muscle strongly correlates with
the oxidative or endurance capacity of the muscle (91,92). In humans it is well established that
exercise conditions result in an increase of capillaries per muscle fiber and an increase in
capillaries per millimeter squared of muscle tissue (92). On the other hand immobilization results in
a decrease in vascular density (93). Is this also the case in the situation of heart failure? Several
studies, using either animal models (94) or investigating skeletal muscle biopsies obtained from
patients with CHF (83,95,96), demonstrated that the capillary density per muscle fiber is
significantly reduced. A possible explanation for the vascular rarefaction may be an increase in
endothelial apoptosis (94) or the reduction in angiogenic growth factors like vascular endothelial
growth factor (VEGF) (for review see 97). Upon an exercise training program an upregulation of
VEGF (98) and subsequently an increase of vascular capillaries was noted (97,99).

9. PERSPECTIVE
During the last years the knowledge of molecular alterations occurring in the skeletal muscle of
patients with CHF after an enrollment into an exercise program has dramatically increased. It is
recognized that exercise training has an influence on fiber type composition of the skeletal muscle
and exerts an anti-inflammatory effect. Furthermore, it is anti-catabolic, via an increase in IGF-1
expression and a downregulation of the ubiquitin-proteasome system and an inhibition of
apoptosis. On the energetic site exercise training favors the expression of oxidative enzymes and
the energy transfer via mitochondrial creatine kinase. A schematic drawing of the effects of
exercise training on the skeletal muscle is depicted in Figure 1. All these beneficial effects on the
skeletal muscle in conjunction with alterations in endothelial function and central hemodynamics
lead to a reduction in mortality (100) and an improvement in quality of life.

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Key Words: Chronic Heart Failure, Skeletal Muscle, Gene Expression, Exercise Training, Review

Send correspondence to: Volker Adams, PhD, University Leipzig, Heart Center Leipzig,
Strumpellstrasse 39, 04289 Leipzig, Tel: 49341865-1671, Fax: 49341865-1461, E-mail:
adav@medizin.uni-leipzig.de