COPD as a Muscle Disease

Michael B. Reid, Ph.D.

Baylor College of Medicine, Houston, Texas

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Artists have much to teach us about respiratory pathophysiology. In his classic depiction of advanced emphysema (1), Dr. Frank Netter provides distinct cues that breathing is labored. The gentleman's lips are pursed and he sits with his shoulder girdle braced. However, the most striking physical sign is an asthenic phenotype, with obvious weight loss and marked atrophy of the trunk and limb muscles. This image clearly illustrates the muscle loss that commonly occurs in chronic obstructive pulmonary disease (COPD) and results in muscle dysfunction (2).

The mechanisms responsible for muscle dysfunction in COPD include the chronic effects of inflammatory mediators (2). In particular, skeletal muscle is exposed to increased concentrations of reactive oxygen species (ROS) that can inhibit force production, contribute to premature muscle fatigue, and promote muscle atrophy. Such responses require that ROS concentrations exceed the buffering capacity of antioxidants in skeletal muscle. The most important antioxidant is glutathione (GSH), a low-molecular-weight molecule present in muscle at millimolar concentrations. GSH inactivates ROS and other biologic oxidants, forming glutathione disulfide (GSSG) as the oxidation by-product. GSSG is then recycled enzymatically to GSH. This cycle is dynamic; GSH is continually being oxidized to GSSG and resynthesized within mammalian cells. The GSH/GSSG cycle plays a fundamental role in cellular homeostasis. Indeed, the balance between GSH and GSSG can be used to assess overall redox environment of the cell (3).

In the current issue (pp. 1114-1118), Rabinovich and associates (4) provide new evidence that GSH regulation is abnormal in muscles of patients with COPD. These investigators tested the postulate that GSH buffering capacity could be enhanced in the lower limb muscles by exercise training. The 8-wk protocol of high-intensity training had the expected effect in control subjects. Compared with the untrained state, the trained vastus lateralis muscle maintained GSH at significantly higher levels after a bout of exhaustive exercise. Thus, training appeared to increase the efficacy of antioxidant buffering in control subjects as expected (5). No such benefit was seen in individuals with COPD. GSH concentrations measured after exhaustive exercise were unaltered by training. Worse, training increased the GSSG levels measured after exhaustive exercise.

The latter finding is paradoxical. Accumulation of the oxidized GSSG molecule suggests that training can be disadvantageous in patients with COPD, making the muscles more susceptible to exercise-induced oxidative stress. How might this be? Where did the system go wrong? The data of Rabinovich and associates provide us with several clues: First, before exercise, GSH and GSSG concentrations in the muscles of trained patients with COPD were not different from the values obtained in trained control subjects. This argues that training did not induce GSH depletion. Nor does it appear that oxidative stress in the lungs or other remote organs starved the muscle of circulating substrate for GSH synthesis. Second, the loss of GSH/GSSG regulation was closely correlated with the gain in exercise capacity produced by training. The strenuous contraction required for skeletal muscle training causes the muscles to generate oxidants at an accelerated rate (6). In patients with COPD, it appears that the increased oxidant production was not adequately buffered. The data suggest that antioxidant buffering did not fully adapt to the higher rate of production, leaving the trained muscle more susceptible to oxidative stress.

Which regulatory element failed to respond? The most obvious candidates are the enzymes that regulate GSH/GSSG cycling. Rabinovich and associates recognized this possibility and measured messenger ribonucleic acid (mRNA) concentrations for a key enzyme in GSH synthesis, -glutamylcysteine synthetase. Results of this analysis were not conclusive, however, and inadequate adaptation of the GSH/GSSG cycle cannot be ruled out. It is equally plausible that training compromised other antioxidant pathways that work in conjunction with GSH. For example, catalase, the superoxide dismutases, -lipoic acid, and vitamins E and C all contribute to antioxidant buffering. Losses in one or more of these pathways would increase the oxidative burden on GSH metabolism, predisposing the muscles to GSSG accumulation during exercise.

So what? Why might we care that GSSG concentrations rise during exercise? The obvious answer lies at the level of muscle function. The rise in GSSG indicates that antioxidant buffering is less effective and that activity of unbuffered oxidants is increased in the working muscle. Oxidants act directly on muscle myofilaments to decrease force production and predispose muscles of the respiratory pump and limbs to premature fatigue (7). Over the long haul, chronic increases in oxidant levels can also influence skeletal muscle gene expression (8). Deleterious effects that may result include accelerated muscle atrophy (9). If training predisposes the muscles of patients with COPD to such effects, it could be wildly counterproductive. Thus, the data of Rabinovich and associates call into question the basic strategy of exercise training for patient rehabilitation.

What is to be done? It is clear that additional data are needed to flesh out this limited but very stimulating report. Assuming the data are reproducibleand there is no reason to suppose otherwiseit becomes important to define the problem in greater detail. We need to know the extent to which training induces antioxidant insufficiency, the antioxidant pathways that are affected, and the degree to which antioxidant deficiency is linked to a specific training regimen. This information may make it possible to avoid antioxidant depletion by tailoring the training protocols appropriately. Alternatively, it may be possible to provide nutritional or pharmacologic supplements that limit oxidative stress in working muscle. The latter intervention has been considered in COPD for pulmonary pharmacotherapy (10) and may also prove beneficial for muscles.

Like Dr. Netter's painting, the data of Rabinovich and associates remind us that lung disease has remote effects on skeletal muscle. It has long been recognized that redox homeostasis is jeopardized by COPD. Rabinovich and associates have provided new evidence to reinforce this principle and to pointedly illustrate its unexpected impact on the muscles of patients.

	References

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1. Netter FH. Respiratory system. In: Divertie MB, editor. 2nd ed., vol. 7, The CIBA Collection of Medical Illustrations. Summit, NJ: CIBA Pharmaceutical Co., 1980. p. 148. 

2. American Thoracic Society and European Respiratory Society. Skeletal muscle dysfunction in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1999;159:S1-S40.

3. Schafer FQ, Buettner GR. Redox environment of the cell as viewed through the redox state of the glutathione disulfide/glutathione couple. Free Rad Biol Med 2001; 30: 1191-1212 [Medline].

4. Rabinovich RA, Ardite E, Troosters T, Carbo N, Alonso J, Gonzalez de Suso JM, Vilaro J, Barbera JA, Polo MF, Argiles JM, Fernandez-Checa JC, Roca J. Reduced muscle redox capacity after endurance training in COPD patients. Am J Respir Crit Care Med 2001; 164: 1114-1118 [Abstract/Free Full Text].

5. Powers SK, Ji LL, Leeuwenburgh C. Exercise training-induced alterations in skeletal muscle antioxidant capacity: a brief review. Med Sci Sports Exerc 1999; 31: 987-997 [Medline].

6. Clanton TL, Zuo L, Klawitter P. Oxidants and skeletal muscle function: physiologic and pathophysiologic implications. Proc Soc Exp Biol Med 1999; 222: 253-262 [Abstract/Free Full Text].

7. Reid MB. Redox modulation of skeletal muscle contraction: what we know and what we don't. J Appl Physiol 2001; 90: 724-731 [Abstract/Free Full Text].

8. Jackson MJ. Free radicals in skin and muscle: damaging agents or signals for adaptation? Proc Nutr Soc 1999; 58: 673-676 [Medline].

9. Kondo H. Oxidative stress in muscular atrophy. In: Sen CK, Packer L, Hanninen O, editors. Handbook of oxidants and antioxidants in exercise. New York: Elsevier; 2000. p. 631-653.

10. Buhl R, Meyer A, Vogelmeier C. Oxidant-protease interaction in the lung: prospects for antioxidant therapy. Chest 1996; 110: 267S-272S [Abstract/Free Full Text].