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* From the Division of Respiratory and Critical Care Physiology and Medicine, Harbor-UCLA Medical Center, Torrance, CA.
Correspondence to: Richard Casaburi, PhD, MD, FCCP, Box 405, Harbor-UCLA Medical Center, 1000 W. Carson St, Torrance, CA 90509; e-mail: casaburi{at}ucla.edu
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Abstract |
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 TOP Abstract IntroductionEvidence for Skeletal Muscle...Possible Mechanisms of Muscle...Exercise Training Yields...Anabolic Hormone Supplementation...References |
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Key Words: anabolic • COPD • exercise • growth hormone • muscle • strength • testosterone
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Introduction |
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TOPAbstractIntroductionEvidence for Skeletal Muscle...Possible Mechanisms of Muscle...Exercise Training Yields...Anabolic Hormone Supplementation...References |
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Abbreviation: IGF = insulin-like growth factor
Advanced COPD burdens the patient with disabling dyspnea and a host of other symptoms and, because of the high worldwide prevalence of cigarette smoking, the number of afflicted individuals is staggering. Consider how few effective therapies we have to offer our patients afflicted with this miserable disease. Inhaled bronchodilators offer distinct, albeit modest, relief to the majority of patients. Thanks in substantial part to the individual for whom this conference is named, Dr. Thomas L. Petty, we recognize that chronic oxygen therapy is of value for the hypoxemic COPD patient. Does the list end with these two therapies? Lung volume reduction surgery, though much discussed,1 remains both unproven and unlikely to be an option for the majority of patients. What of the efforts of our colleagues, the cellular and molecular biologists? It may be uncharitable to point out that, despite almost 15 years of siphoning the vast majority of pulmonary science research dollars into cell and molecular biology pursuits, we have no therapies for COPD in hand.
I would argue that pulmonary rehabilitation and, specifically, rehabilitative exercise training should join this short list of therapies with demonstrated efficacy. This argument is much easier to make today than it was 10 years ago. If we consider COPD to be exclusively a disease of the lung, it is hard to understand how exercise training would be of help. Clearly, exercise training does nothing to improve pulmonary mechanics, pulmonary gas exchange, or pulmonary vascular function. Formerly, it was conceded that exercise programs were primarily of psychological value, of use in motivating patients toward a higher level of activity. The current view, however, is to consider COPD a multiorgan system disease. In particular, there is accumulating evidence that the skeletal muscles (most importantly, the muscles of ambulation) do not function normally and that this dysfunction contributes to exercise intolerance. Exercise intolerance is often the COPD patient’s chief complaint.2 In this view, rehabilitative exercise training has the goal of treating skeletal muscle dysfunction. Moreover, there are other therapies that might ameliorate skeletal muscle dysfunction, and these might be suitable for administration in the context of pulmonary rehabilitation.
This review will summarize the following evidence obtained to date: (1) skeletal muscle dysfunction is present in COPD; (2) the dysfunction may be multifactorial; (3) exercise training can yield physiologic improvements in muscle function; and (4) anabolic hormone supplementation is rational therapy for this disorder. This topic has also been recently addressed in a Statement of the American Thoracic Society and European Respiratory Society,3 which was composed by an international panel of experts.
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Evidence for Skeletal Muscle Dysfunction in COPD |
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TOPAbstractIntroductionEvidence for Skeletal Muscle...Possible Mechanisms of Muscle...Exercise Training Yields...Anabolic Hormone Supplementation...References |
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2. Several investigators have shown that lactic acidosis occurs at much lower work rates than in healthy subjects.9 11 Evidence supporting this observation is obtained from magnetic resonance spectroscopy; fall in muscle pH occurs at low work rates.12 Lactic acid accumulates when oxygen transport to the exercising muscle becomes inadequate, and anaerobic glycolysis is called on to supplement aerobic adenosine triphosphate production. Recent studies show that bulk oxygen transport to the lower extremities appears to be adequate.13 Therefore, intrinsic abnormalities in the exercising muscles seem to be implicated. Early onset of lactic acidosis can impair the exercise tolerance of COPD patients, in that lactic acid is a ventilatory stimulant, increasing the ventilatory requirement for exercise.14
3. Although the oxygen-uptake requirements in the steady-state of exercise likely do not differ substantially in the COPD patient as compared to the healthy subject,15 16 the kinetics of oxygen uptake are markedly slow.16 17 When exercise begins, the oxygen demands of the muscle rise abruptly, but the oxygen extraction from the muscle capillary blood (and the oxygen extraction from the environment) does not reach a steady state for several minutes. This delay constitutes an oxygen debt; a large oxygen debt connotes poor aerobic function.
4. Several surgical series have shown that exercise intolerance remains prominent after single or double lung transplantation. After transplantation, lung mechanics and gas exchange are improved considerably (or even normalized), and the ventilation the patient can sustain no longer limits exercise tolerance. Despite this, exercise intolerance is still present; peak oxygen uptake averages only 40 to 50% predicted.18 The most reasonable hypothesis to explain this substantial degree of residual exercise intolerance is skeletal muscle dysfunction, although it must be allowed that immunosuppressive drugs that transplant recipients must take may contribute to poor muscle function.
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Possible Mechanisms of Muscle Dysfunction |
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TOPAbstractIntroductionEvidence for Skeletal Muscle...Possible Mechanisms of Muscle...Exercise Training Yields...Anabolic Hormone Supplementation...References |
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2. Malnutrition may contribute to inability to synthesize muscle protein and may be responsible, in part, for the profound muscle wasting seen in some patients.21 However, recent research indicates that inflammatory mediators are elevated in some COPD patients,22 and it is speculated that these mediators may be responsible for weight loss and muscle wasting.
3. Adequate levels of anabolic hormones are required for normal muscle growth and development. There are two well-described anabolic hormone systems. Growth hormone, secreted by the pituitary, has an anabolic effect on muscles principally through stimulating production of insulin-like growth factor (IGF)- 1.23 In men, testosterone is secreted by the testes and has a substantial anabolic effect on muscle. In women, testosterone plays a less well-understood role; circulating levels are roughly tenfold lower than in men.24 However, some investigators have started to consider the feasibility of testosterone administration to women.25 In healthy elderly subjects, levels of both IGF-1 and testosterone tend to be lower than in the young.26 27 Preliminary evidence reveals a considerable prevalence of substantially reduced levels of these circulating hormones in COPD patients.28 29
4. Corticosteroids are known to cause muscle weakness. Both acute and chronic steroid myopathies have been described. The former is a profound general muscle weakness, uncommonly seen several days after treatment with high doses of IV corticosteroids.30 Chronic steroid myopathy is a more common occurrence, seen after prolonged administration of lower doses of corticosteroids.31 The time course of reversal of chronic steroid myopathy is unclear; it seems possible that many months may be required.
5. It is altogether possible that there is a specific myopathy associated with COPD. Chronic hypoxemia or hypercapnia3 or the effects of cigarette smoking could conceivably damage the muscles. Comorbid conditions may also play a role. Electrolyte imbalance is known to impair skeletal muscle function.32 Cardiac failure is known to induce changes in muscle structure,33 although these data have been gathered in patients with congestive heart failure, not cor pulmonale.
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Exercise Training Yields Improvements in Muscle Function in COPD |
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TOPAbstractIntroductionEvidence for Skeletal Muscle...Possible Mechanisms of Muscle...Exercise Training Yields...Anabolic Hormone Supplementation...References |
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1. Muscle biopsies performed before and after a rigorous endurance training program have demonstrated that concentrations of the enzymes facilitating oxidative metabolism are increased.34
2. A given level of heavy exercise can be performed with a smaller increase in blood lactic acid level after a training program.11 35 36 This is associated with a proportionally lower level of carbon dioxide output and of ventilation.11
3. After a training program, following the onset of constant work rate exercise, the kinetics of oxygen uptake are faster.17 This indicates better aerobic function of the muscles.
These physiologic improvements in muscle function only occur after a rigorous program of endurance training. Though physiologically based principles for exercise prescription in COPD patients have not been fully defined,37 certain principles are likely to be true. As in healthy subjects, programs need to last for 5 to 8 weeks, sessions need to be held 3 to 5 times per week, and sessions need to be 30 to 45 min in duration to achieve a substantial aerobic training effect.38 Exercise intensity prescription is controversial, but some authors have posited that high fractions of the peak work rate achievable (perhaps 75 to 85%) is an achievable goal.39 Such training programs have been shown to yield substantial increases in exercise tolerance in patients with both moderate and severe COPD.11 17
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Anabolic Hormone Supplementation is Rational Therapy for COPD Patients |
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TOPAbstractIntroductionEvidence for Skeletal Muscle...Possible Mechanisms of Muscle...Exercise Training Yields...Anabolic Hormone Supplementation...References |
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When growth hormone is given to growth hormone-deficient adults, muscle mass increases and strength improves. In healthy young subjects, growth hormone administration causes muscle protein synthesis to increase.43 In healthy older subjects and patients with HIV-wasting syndrome, growth hormone yields increases in muscle mass.44 45 However, studies of functional capabilities have yielded mixed results. In COPD, a 3-week study of thrice-weekly growth hormone administration found evidence of increased muscle mass, but no change in endurance exercise capacity.46 Because growth hormone must be administered by injection several times per week, because it is quite expensive, and because of equivocal evidence of improved exercise tolerance, questions have been raised regarding the usefulness of growth hormone as therapy for patients with chronic disease.47
The administration of testosterone to men whose testicular production is inadequate clearly increases muscle mass and strength.48 However, the widespread use of anabolic steroids by athletes and body builders has generated nearly a half century of controversy. It was widely believed by the sports medicine community that supraphysiologic doses of testosterone yield muscle hypertrophy and improved performance. Anecdotal evidence of effectiveness, followed by the publication of > 12 studies conducted mostly in the 1970s, proved inconclusive.49 However, the issue seems to have been settled by a publication of a randomized, well-controlled 10-week trial of supraphysiologic doses of testosterone enanthate delivered in weekly injections.50 Lean body mass and muscle strength increased substantially, and strength training yielded additive effects. Only a few studies have examined the effect of anabolic steroids in patients with chronic disease. In men with AIDS-wasting syndrome, replacement doses of testosterone increased lean body mass, but the change in the 6-min walk distance was not significantly different from the control group.51 Nandrolone (an orally administered anabolic steroid) or placebo was given to 217 men and women with COPD.52 A small increase in lean body mass and a small increase in maximum inspiratory pressure was seen in the nandrolone group. Recently, 6 months of oral stanozolol yielded a mean 1.8-kg increase in lean body mass but no increase in endurance exercise tolerance in 10 underweight COPD patients.53 Before anabolic steroids can be routinely prescribed for patients with COPD, safety concerns must be addressed.54 55 There is a theoretic risk that an occult prostate malignancy might be stimulated to grow faster, although fairly large studies of elderly men are reassuring. Since testosterone stimulates erythrocyte production,56 a tendency toward polycythemia might be exacerbated.
In summary, curing the dysfunction of the peripheral musculature of patients with COPD may in the near future become a routine part of the therapeutic plan. Research into the nature of the defect in muscle function, optimal exercise strategies, and more beneficial anabolic drugs is likely to be productive.
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Footnotes |
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References |
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TOPAbstractIntroductionEvidence for Skeletal Muscle...Possible Mechanisms of Muscle...Exercise Training Yields...Anabolic Hormone Supplementation...References |
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