Exercise training and skeletal muscle inflammation in chronic heart failure

feeling better about fatigue

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-κB), 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-κB-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 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 UTP-end 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 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 Journalillustrate 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 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.