Peripheral Muscle Wasting in Chronic Obstructive Pulmonary Disease
Clinical Relevance and Mechanisms

RICHARD DEBIGARÉ, CLAUDE H. CÔTÉ, and FRANÇOIS MALTAIS

Centre de Recherche, Hôpital Laval, Institut Universitaire de Cardiologie et de Pneumologie de l'Université Laval and Centre de Recherche, CHUL, Centre Hospitalier Universitaire de l'Université Laval, Sainte-Foy, Canada

	INTRODUCTION

TOP INTRODUCTION CLINICAL SIGNIFICANCE OF MUSCLE... MUSCLE WASTING AND CACHEXIA... PROPOSED MECHANISMS LEADING TO... SYSTEMIC MECHANISMS OF CACHEXIA... POTENTIAL THERAPEUTIC AVENUES SUGGESTIONS FOR FURTHER... SUMMARY REFERENCES

Peripheral muscle wasting is a common finding in advanced chronic obstructive pulmonary disease (COPD) and several other chronic diseases. Although muscle wasting has long been recognized by clinicians (1), its relevance to patients' outcome and management has been overlooked. There is a renewed interest in this problem in respiratory and other chronic diseases as recent advances in clinical research have confirmed the negative impact of muscle wasting on patient survival (2, 3). At the same time, exciting and innovative research in molecular biology is improving our understanding of how muscle mass is maintained (4, 5). Effective treatment for muscle wasting has yet to be developed, but there is now evidence, from animal and human studies, that muscle mass may be manipulated with success in wasting disorders (4). As a result of this research, new molecules specifically targeted at maintaining or increasing muscle mass in patients with COPD or other chronic conditions should become available in the future. In this pulmonary perspective, the clinical significance of muscle wasting associated with COPD will be briefly reviewed, taking into account the knowledge obtained from the study of other chronic diseases. Based upon new developments in molecular biology, possible mechanisms leading to muscle wasting and potential therapeutic strategies will be presented as well as suggestions for future research. It is not the scope of the present study to provide a complete review of the literature on peripheral muscle function in COPD, which can be found elsewhere (6, 7).

	CLINICAL SIGNIFICANCE OF MUSCLE WASTING IN COPD

TOP INTRODUCTION CLINICAL SIGNIFICANCE OF MUSCLE... MUSCLE WASTING AND CACHEXIA... PROPOSED MECHANISMS LEADING TO... SYSTEMIC MECHANISMS OF CACHEXIA... POTENTIAL THERAPEUTIC AVENUES SUGGESTIONS FOR FURTHER... SUMMARY REFERENCES

Available information suggests that muscle wasting is present in a large population of patients with COPD but its prevalence can only be approximated as there are no simple techniques to measure muscle mass. In one study, reduced body weight was reported in up to 49% of 253 patients with COPD involved in pulmonary rehabilitation (8). However, the actual prevalence and magnitude of muscle wasting are probably underestimated when extrapolated from body weight measurements since lean body mass, an index of muscle mass, may be reduced despite preservation of body weight (8). This conclusion is further supported by data showing a proportionally greater reduction in thigh muscle cross-sectional area than body weight (9), indicating a preferential loss of muscle tissue over other body compartments in emaciated patients with COPD. Low muscle mass in COPD is associated with weaker peripheral muscles, impaired functional status (9), as well as poor health-related quality of life (10). The reduction in peripheral muscle mass and strength is of similar magnitude in COPD (9) suggesting that the remaining contractile apparatus is functionally preserved. This may not be the case for patients frequently exposed to systemic corticosteroids in whom the loss of strength may be out of proportion to the reduction in muscle mass (9, 11). Interestingly, the strength of the quadriceps is an important correlate of exercise tolerance in COPD (12). This can be explained by the influence of muscle strength on the perception of leg effort during exercise, which is the main limiting symptom in 40-45% of patients with COPD (12). Importantly, emaciation is a powerful predictor of mortality in COPD, independent of the impairment in lung function (2). Based on the established relationship between body weight and survival (2), and on the observation of a preferential loss of muscle tissue in COPD (9), it can be speculated that muscle wasting is also a strong predictor of mortality in COPD.

Muscle Wasting in COPD: Nutritional Imbalance or Cachexia?

Increased resting energy expenditure is a common finding in COPD (13, 14) and it is often assumed that wasting is the consequence of an imbalance between energy intake and expenditure. However, in several patients, the importance of this factor may be downplayed by a decrease in daily activities (13) so that their total energy expenditure is actually not different compared with healthy subjects (14). In addition, nutritional supplementation in COPD has failed to induce any clinically meaningful increase in muscle mass in the majority of patients (15). Cachexia (poor condition in Greek) differs from simple nutritional imbalance and starvation by the presence of important modifications in the metabolism of proteins, lipids, and carbohydrates presumably related to systemic inflammation (16). Other characteristic features of cachexia, also found in COPD, that cannot be currently explained on the basis of nutritional imbalance, include preferential loss of muscle tissue over fat, enhanced protein degradation (17), and unresponsiveness to nutritional interventions (15, 16). Clearly, muscle wasting in COPD has many more similarities with cachexia than with starvation and nutritional imbalance.

	MUSCLE WASTING AND CACHEXIA IN OTHER CHRONIC DISEASES

TOP INTRODUCTION CLINICAL SIGNIFICANCE OF MUSCLE... MUSCLE WASTING AND CACHEXIA... PROPOSED MECHANISMS LEADING TO... SYSTEMIC MECHANISMS OF CACHEXIA... POTENTIAL THERAPEUTIC AVENUES SUGGESTIONS FOR FURTHER... SUMMARY REFERENCES

Infectious disease specialists (18), cardiologists (3), and nephrologists (19), among others, have recognized for quite a while the importance of muscle wasting for their patients and this is reflected by a large body of research on cachexia and its treatments (20, 21). Chronic heart (CHF) (3) and renal failures (CRF) (19), acquired immunodeficiency syndrome (AIDS) (18), cancer (16), and several other disease states can all be associated with muscle wasting (21). Indeed, in CHF and CRF, cachexia is a strong independent risk factor for mortality (3, 19). Up to one-third of all cancer patients die from direct consequences of cachexia and not from cancer itself (16) while in AIDS, a weight loss of as little as 5% over a 4-mo period is associated with an increased risk of death and opportunistic infections (18). Beyond a reduced survival rate, cachexia is also related to poor functional status and health-related quality of life in these conditions (16, 21). The observation that cachexia is a common final scenario of several chronic conditions, including COPD, suggests some similarities in the underlying mechanisms (20). One of these similarities is a low plasma level of anabolic hormones such as insulin-like growth factors (IGFs) and testosterone (21). Another common feature of all these chronic diseases is the presence of systemic and/or local inflammation. Circulating levels of tumor necrosis factor- (TNF-), interleukin-1 (IL-1), interleukin-6 (IL-6), interleukin-8 (IL-8), interferon- (INF-) and other proinflammatory molecules (16) are increased in patients suffering from CHF (3), CRF (19), cancer (16), and AIDS (18) and are thought to be factors contributing to the establishment of cachexia. Although it is tempting to speculate that these circulatory cytokines are mainly produced by the primary diseased organ (16), their origin has not been clarified and how they can influence muscle mass is still a nebulous issue.

	PROPOSED MECHANISMS LEADING TO CACHEXIA: BASIC RESEARCH

TOP INTRODUCTION CLINICAL SIGNIFICANCE OF MUSCLE... MUSCLE WASTING AND CACHEXIA... PROPOSED MECHANISMS LEADING TO... SYSTEMIC MECHANISMS OF CACHEXIA... POTENTIAL THERAPEUTIC AVENUES SUGGESTIONS FOR FURTHER... SUMMARY REFERENCES

As a highly differentiated tissue, it was assumed for a long time that adult muscle fibers had little or no potential to regenerate. However, muscle repair after experimentally induced damages or exercise-induced hypertrophy are examples that muscle homeostasis is a dynamic process between anabolism and catabolism. Animal models and cultured myoblasts have been useful in improving our knowledge of how skeletal muscle homeostasis is regulated at the molecular level. This research may eventually lead to the development of effective treatment for this condition. In the next section, factors influencing muscle catabolism and anabolism will be briefly discussed.

Increased muscle protein breakdown is a key feature in muscle cachexia (20). Extracellular proteins are mainly degraded by acid proteases, such as cathepsins and hydrolases, included in lysosomes. Intracellular proteins can be hydrolyzed by the calcium-dependent calpains, which are activated after muscle damage. The third, and the most relevant proteolytic pathway to muscle wasting, is the ATP-ubiquitin- dependent proteolytic system through which contractile proteins are degraded leading to cachexia (20). This system can be activated by cytokines (22), glucocorticoids (23), acidosis (23), inactivity (24), or low insulin level (23). In this pathway, proteins are initially marked for degradation by ubiquitination, and are subsequently recognized and processed in the proteasome, the catalytic core of the ubiquitin-proteasome pathway. An increase in mRNA encoding for key enzymes and proteins of this pathway is a hallmark of cachexia in several animal models (20). Furthermore, inhibitors of the proteasome have been shown to decrease muscle protein breakdown in several models of cachexia (25).

The signals and initial steps of muscle protein degradation in wasted patients are the subjects of intense research. Evidence that cachexia is triggered endogenously was obtained when muscle wasting was demonstrated in a non-tumor-bearing rat after its blood supply was conjoined with that of a sarcoma-bearing rat (26). Along the same line, several experimental findings suggested that cytokines were involved in cachexia: cultured myoblasts exposed to TNF- or other cytokines do not undergo normal differentiation (27); cachexia can be induced in small animals with systemic injection of proinflammatory cytokines (22), and this can be prevented by inhibiting the activity of these cytokines (28) or their receptors (22). Although proinflammatory cytokines such as TNF- and IL-6 can activate the ubiquitin-proteasome pathway, they do not reduce lean body mass directly. In this regard, the activation of nuclear factor-kappa B (NF-B) seems to be a key intermediate step. NF-B is a ubiquitous transcription factor present in the cytosol in an inactive form when coupled to its natural inhibitor, IB. Inflammatory cytokines can activate NF-B by initiating the degradation of IB by the proteasome. Free of its inhibitor, NF-B can then translocate into the nucleus, bind to target DNA elements, and regulate the transcription of several genes coding for inflammatory and growth molecules (29). In muscle, NF-B can inhibit MyoD expression, which is a transcription factor that is essential and specific for skeletal muscle differentiation, and repair (27). Direct inhibition of NF-B prevents cachexia in animal models (27). The negative action of NF-B on muscle growth and repair is submitted to tight counterregulation mechanisms. For instance, NF-B can also suppress the transcription of the proteasome C3 subunit in muscle cells, thus blocking muscle protein degradation (23). Interestingly, glucocorticoids exert their catabolic effect by opposing the NF-B proteasome suppression (23). In summary, basic research has provided solid evidence for the concept of cytokine activation of the ubiquitin- proteasome pathway resulting in a catabolic state and eventually in cachexia, regardless of the initial pathological process. However, this complex catabolic cascade involves several intricate components and more studies need to be done to understand their specific role and how they interact.

Proinflammatory cytokines may also exert part of their negative effects on muscle mass by increasing the production of reactive oxygen species (ROS). Skeletal muscle proteins modified by these ROS can be easily degraded by the proteasome (30). Interestingly, antioxidants may prevent muscle wasting in a murine model of cachexia induced by TNF- (4). Thus, inflammation and ROS may have interrelated actions and act synergistically in inducing muscle proteolysis.

Although increased catabolism is a hallmark of cachexia, there is also support for the hypothesis that anabolic factors are equally important for muscle homeostasis. A mechanistic link between anabolic factors and the maintenance of muscle mass is emerging. For instance, it was recently demonstrated that insulin and IGFs stimulate myofibril synthesis (31). IGFs can also decrease protein degradation by reducing the activity of the ubiquitin-proteasome pathway (32). The persistent expression of insulin-like growth factor-I (IGF-I) in senescent muscle sustains their initial hypertrophy and regeneration (7). Interestingly, proinflammatory cytokines can exert a suppressive action on IGF-I by up-regulating the expression of its circulatory inhibitor, insulin-like growth factor binding protein-1 (33). This indicates that there is a close relationship between the catabolic and anabolic pathways. Other factors regulating muscle growth such as myostatin and myogenin have recently been identified and their role in wasting disorder is currently being investigated (34, 35).

In theory, low protein intake associated with increased energy expenditure could lead to an imbalance between catabolism and anabolism and, thereby, lead to cachexia. However, the levels of nutrient intake and resting energy expenditure found in various wasting disorders can be increased, normal, or decreased (16, 21). In addition, several studies failed to demonstrate a clear effect of nutritional intervention on muscle mass (16, 21). These observations make it difficult to conclude that nutritional imbalance is a key element in the cachectic process.

	SYSTEMIC MECHANISMS OF CACHEXIA IN COPD

TOP INTRODUCTION CLINICAL SIGNIFICANCE OF MUSCLE... MUSCLE WASTING AND CACHEXIA... PROPOSED MECHANISMS LEADING TO... SYSTEMIC MECHANISMS OF CACHEXIA... POTENTIAL THERAPEUTIC AVENUES SUGGESTIONS FOR FURTHER... SUMMARY REFERENCES

Like several other chronic diseases, COPD is characterized by low grade systemic inflammation (36) that is often accompanied by low blood levels of anabolic hormones (39, 40). Elevated blood levels of IL-6 (37), IL-8 (37), TNF- (36), and C-reactive protein (37) in patients with COPD have been associated with increased resting energy expenditure (37) and unresponsiveness to nutritional interventions, giving support to the concept that these cytokines play a role in COPD-associated cachexia. In addition, adhesion molecules are increased in bronchoalveolar fluids and in plasma of patients with COPD compared with healthy subjects (38). The presence of adhesion molecules in the blood is necessary for the initiation of bronchial inflammatory cell infiltration. In theory, these adhesion molecules could also induce inflammatory cell infiltration in other tissues such as skeletal muscle, but this has yet to be verified. In view of the possible interaction between proinflammatory cytokines and ROS, it is interesting to consider that increased generation of ROS, probably originating from the contractile muscles, has been reported after low-intensity exercise in COPD (41). Thus, repeated bursts of ROS occurring within the peripheral muscles of patients with COPD during activities of daily living may be involved in triggering the cachexic cascade.

Although there is a low grade of systemic inflammation in patients with COPD, they also show a higher prevalence of low plasma levels of testosterone (39) and IGF-I (40) compared with healthy subjects of similar age. The clinical relevance of this finding remains to be elucidated as correlations between body weight or muscle mass and plasma level of these hormones are weak (39) and supplementation of anabolic steroids (15) or growth hormone (42) had only a modest effect on lean mass and functional status, perhaps because of a defective hormonal receptor. To clarify the implication of low anabolic hormone levels in cachexia, data on the muscle concentration of these molecules as well as information on their specific cellular receptors in wasted subjects are required.

Hypoxemia, either chronic or intermittent, is a common finding in COPD and may influence skeletal muscle homeostasis in several ways as it does in healthy individuals exposed to hypoxic environment (43). Hypoxemia may contribute to wasting in COPD by decreasing the anabolic hormone level (44) with an opposite effect on proinflammatory cytokines (45). The presence of hypoxemia is also associated with the generation of ROS contributing to oxidative stress (41). Overall hypoxemia may contribute to wasting by displacing the balance between anabolic/catabolic factors in favor of the latter.

Whether proinflammatory cytokines alone can induce cachexia on their own is debatable since the plasma concentration observed is much lower than what is required to induce cachexia in animal studies (4). In addition, there is no demonstration of increased concentration or activities of proinflammatory cytokines within the muscles of wasted patients with COPD or other chronic illnesses. The relative preservation of some muscle groups such as the diaphragm (46) is also difficult to explain if a systemic etiology is proposed for muscle wasting. The preferential involvement of some muscle groups suggests that local muscle factors must be involved in the development of cachexia.

Inactivity, perhaps the most obvious local factor, may increase the activity of the ubiquitin-proteasome pathway (24) and decrease the production and responsiveness to IGFs (47). Other local factors, yet to be identified, are possibly involved in muscle wasting as indicated by the marked modifications in the myosin heavy chain profile in the vastus lateralis of patients with COPD compared with healthy subjects despite only modest differences in physical fitness (48). Maybe the most provocative observation in this regard is the decreased hindlimb muscle oxidative capacity found in the emphysematous hamster despite the absence of a reduction in their level of activity compared with control animals (49). As indicated above, ROS may act locally to trigger muscle wasting. In addition, a few studies suggest that muscle acidosis may be involved in protein degradation (20, 23). This may be relevant to patients with COPD in whom mild exercise, such as those performed in daily living, induces early and exaggerated muscle acidosis compared with healthy subjects (50).

A reasonable integrative hypothesis is that cachexia in COPD is the result of an interplay of systemic factors (e.g., cytokines, growth factors) that although not remarkably elevated, may synergize with local factors (e.g., inactivity, ROS, acidosis) leading to a disequilibrium between anabolism and catabolism. A simplified but useful schematic representation of the cellular mechanisms of muscle wasting in COPD is proposed in Figure 1. Further studies are warranted to determine the relative importance of all the potential factors involved in this complex process.

View larger version (58K): [in this window] [in a new window]   Figure 1.   Schematic representation of the possible mechanisms of cachexia in COPD. Growth factors such as insulin-like growth factor-I (IGF-I) and MyoD have their anabolic effects by activating myofibrils synthesis. Myofibrillar proteins are marked for degradation by ubiquitin (Ub) and are then processed through the 26 S proteasome. This protein degradation pathway can be activated by muscle inactivity. Proinflammatory cytokines such as TNF (shown here), IL-1, and IL-6, for instance, exert their catabolic action by activating NF-B, which can enter the nucleus after dissociating from its inhibitor (IB). One catabolic action of NF-B is to repress the gene expression of MyoD. Proinflammatory cytokines may also activate the ubiquitin-proteasome pathway. A reasonable hypothesis is that systemic (TNF, growth factors) as well as local factors (inactivity, acidosis) interact in the development of cachexia. Ub = ubiquitin; NF-B = nuclear factor B; IB = NF-B natural inhibitor; MHC = myosin heavy chain; IGF = insulin-like growth factor; IGFR = insulin-like growth factor receptor; TNF = tumor necrosis factor; TNFR I and II = tumor necrosis factor receptor I and II.

	POTENTIAL THERAPEUTIC AVENUES

TOP INTRODUCTION CLINICAL SIGNIFICANCE OF MUSCLE... MUSCLE WASTING AND CACHEXIA... PROPOSED MECHANISMS LEADING TO... SYSTEMIC MECHANISMS OF CACHEXIA... POTENTIAL THERAPEUTIC AVENUES SUGGESTIONS FOR FURTHER... SUMMARY REFERENCES

It is important to recognize the potential therapeutic consequences of peripheral muscle wasting. Gain in muscle mass and strength has been associated with better exercise tolerance and survival (2). Thus, improving peripheral muscle function could be a reasonable therapeutic target in patients with COPD. Probably the best available therapeutic modality to preserve muscle mass is strength training as physical activity can decrease proteasome activity (51). Anabolic steroids (15) and growth hormone (42) supplementation have been disappointing so far. However, the doses utilized were most likely subtherapeutic and further studies are needed to determine optimal dosage of these anabolic hormones. The use of these drugs should also be studied in conjunction with exercise training as synergy may be observed.

Based on the current knowledge of muscle homeostasis, several novel therapeutic avenues can be proposed to reverse the wasting process and its deleterious consequences on survival. So far, very few of them have been investigated clinically (21, 52, 53). One way to intervene is to increase protein synthesis using growth factors such as IGF-I, which can suppress the ubiquitin and proteasome activities (54) and induce hypertrophy (5, 31). Novel forms of nutritional interventions using branched amino acids supplementation (leucine, isoleucine, and valine) appear to be of interest as they may inhibit proteolysis in skeletal muscle by acting as a negative-feedback regulator of the lysosomal proteolytic system and by decreasing ubiquitin-proteasome system gene expression (55). In rats, clenbuterol, a ₂-adrenergic agonist, normalizes protein breakdown and prevents skeletal muscle wasting (56). However, equivocal results have been obtained with this drug in humans (52, 57). Anticytokines, proteasome inhibitors in animals (25) and in human (53), and antioxidants are promising strategies currently under investigation. These are just a few examples of how basic research in cachexia opens up new therapeutic frontiers for our patients.

	SUGGESTIONS FOR FURTHER RESEARCH

TOP INTRODUCTION CLINICAL SIGNIFICANCE OF MUSCLE... MUSCLE WASTING AND CACHEXIA... PROPOSED MECHANISMS LEADING TO... SYSTEMIC MECHANISMS OF CACHEXIA... POTENTIAL THERAPEUTIC AVENUES SUGGESTIONS FOR FURTHER... SUMMARY REFERENCES

Still today, very little is known about the mechanisms and specific treatments of muscle wasting in COPD. In addition, the nature of the link between muscle wasting and survival has not been clarified. The followings are some suggestions for further researches.

1. The negative impact of low muscle mass on clinical outcomes in COPD is inferred only from cross-sectional studies. It is uncertain whether low muscle mass reflects only the severity of the disease or if it is mechanistically linked to survival. Longitudinal studies evaluating how body composition changes with time and how it does influence clinical outcomes would be useful to clarify these issues.

2. The possible role of systemic inflammation, low anabolic hormone levels, or other causal mechanisms (e.g., oxidative stress) on cachexia in COPD is based only upon descriptive data and correlation analyses. There is a need to learn if these factors are only surrogate markers of the disease or if they influence muscle homeostasis directly. How clinical conditions such as hypoxemia and inactivity influence these factors is also unknown.

3. Little or nothing is known about the molecular mechanisms of muscle wasting in COPD. This area will need to be explored if we hope to develop specific treatments for this condition.

	SUMMARY

TOP INTRODUCTION CLINICAL SIGNIFICANCE OF MUSCLE... MUSCLE WASTING AND CACHEXIA... PROPOSED MECHANISMS LEADING TO... SYSTEMIC MECHANISMS OF CACHEXIA... POTENTIAL THERAPEUTIC AVENUES SUGGESTIONS FOR FURTHER... SUMMARY REFERENCES

In this article, the concept that muscle wasting in COPD is in fact a state of cachexia was developed. Muscle wasting should be considered as a serious complication in COPD and other chronic illnesses with important implications for survival. Up to now, there is no effective treatment for this complication but optimism is warranted now that the understanding of the molecular mechanisms of cachexia has evolved. Research on muscle wasting is extremely active and this will eventually lead to the development of specific treatments for cachexia such as proteasome and cytokine inhibition or muscle growth factors. The clinical approach to cachexia in COPD and other chronic diseases should change dramatically in the near future. This is an exciting research area to follow.

	Footnotes

Correspondence and requests for reprints should be addressed to Dr. François Maltais, Centre de Pneumologie, Hôpital Laval, 2725 Chemin Ste-Foy, Ste-Foy, QC, Canada G1V 4G5. E-mail: medfma{at}hermes.ulaval.ca

(Received in original form April 6, 2001 and accepted in revised form July 20, 2001).

Acknowledgments: The authors acknowledge the contributions of Dr. Pierre LeBlanc and Dr. Jean Jobin to the research and thank Drs. Yves Deshaies and S. Russ Price for helpful suggestions regarding the manuscript.

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TOP INTRODUCTION CLINICAL SIGNIFICANCE OF MUSCLE... MUSCLE WASTING AND CACHEXIA... PROPOSED MECHANISMS LEADING TO... SYSTEMIC MECHANISMS OF CACHEXIA... POTENTIAL THERAPEUTIC AVENUES SUGGESTIONS FOR FURTHER... SUMMARY REFERENCES

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