Ovid: Skeletal Muscle Function in COPD*.

Skeletal Muscle Function in COPD*

Casaburi, Richard PhD, MD, FCCP

Section Editor(s): Petty, Thomas L. MD, Master FCCP; Rennard, Stephen I. MD, FCCP

Author Information
*From the Division of Respiratory and Critical Care Physiology and Medicine, Harbor-UCLA Medical Center, Torrance, CA.

Supported by the Tobacco Related Disease Research Program of the University of California.

Correspondence to: Richard Casaburi, PhD, MD, FCCP, Box 405, Harbor-UCLA Medical Center, 1000 W. Carson St, Torrance, CA 90509; e-mail: casaburi@ucla.edu

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Abstract

Few effective therapies exist for patients with COPD. Rehabilitative therapy aimed at curing dysfunction of

the peripheral muscles may be an appropriate addition to this short list. This review does the following: (1)

presents evidence that skeletal muscle dysfunction is present in COPD patients; (2) considers the mechanisms

of this dysfunction; (3) describes the role of exercise training in correcting this disorder; and (4) speculates

that anabolic hormone supplementation may find a place in COPD therapy. Further research will be necessary

to refine these concepts.

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
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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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1. Several recent studies of the vastus lateralis muscle appear to show that structural and biochemical

abnormalities exist in COPD patients, although age- and activity-matched control groups have not always

been employed. A lower fraction of type I fibers (and higher fraction of type II fibers) are present.4,5 A

higher fraction of myosin heavy chain type 2B isoform has been found.6 These findings would predict

relatively poor aerobic function of these muscles. Accentuating the abnormalities in aerobic function,

capillary density is decreased,5,7 which would result in increased diffusion distances for oxygen transport.

Moreover, concentrations of aerobic, but not glycolytic, enzymes are reduced in COPD patients.8,9 These

findings, along with reports that muscle mass is low 10 (often even if the patient is of normal body weight),

are consistent with poor muscle function.

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.

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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

1. Deconditioning almost certainly is a major contributor to the muscle dysfunction seen in COPD patients.19

These patients generally assume an extremely sedentary lifestyle to avoid the dyspnea that activity brings.

Studies of healthy subjects undergoing bed rest or astronauts experiencing prolonged weightlessness have

defined the effects of deconditioning.19,20 The muscles of ambulation atrophy, muscle capillary density falls,

aerobic enzyme concentrations decrease, and a shift in muscle fiber type from type IIa to type IIb is seen.

These changes yield substantial decreases in strength and endurance.

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
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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

hypercapnia 3 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

The past 10 years have seen the accumulation of data supporting the concept that exercise programs are

capable of inducing physiologic changes in the muscles of ambulation that improve exercise tolerance in

COPD. Several pieces of evidence to support physiologic benefit can be cited.

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.

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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

In view of preliminary evidence that COPD patients have low circulating levels of IGF-1 and (in men)

testosterone, hormone supplementation seems an attractive method to reverse muscle dysfunction. However,

not all anabolic stimuli to muscle yield similar effects. For example, endurance and strength training

programs have substantially different effects on the exercising muscles. Endurance programs increase

capillarity, aerobic enzyme concentrations, and mitochondrial number, but do not cause appreciable muscle

fiber hypertrophy. Strength training programs, in contrast, induce dramatic hypertrophy, which increases the

potential for force generation for explosive tasks, but do not yield changes that decrease diffusion distances

for oxygen. Therefore, strength training increases strength and endurance training increases endurance. From

studies in healthy subjects, there is preliminary evidence that both growth hormone and testosterone

administration predominantly induce hypertrophy, similar to a strength training adaptation.40 Though this

conclusion is speculative, it seems unreasonable to expect that either growth hormone or testosterone

administration will increase exercise endurance. However, decreased strength is commonly seen in COPD

patients 41,42 and strength is required for many everyday activities.

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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

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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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References

1 Fessler HE, Wise RA. Lung volume reduction surgery: is less really more? Am J Respir Crit Care Med 1999;

159:1031-1035 Bibliographic Links [Context Link]

2 Casaburi R. Exercise training in chronic obstructive lung disease. In: Casaburi R, Petty TL, eds. Principles

and practice of pulmonary rehabilitation. Philadelphia, PA: WB Saunders, 1993; 204-224 [Context Link]

3 Skeletal muscle dysfunction in chronic obstructive pulmonary disease: a statement of the American Thoracic

Society and European Respiratory Society. Am J Respir Crit Care Med 1999; 159:S1-S40 [Context Link]

4 Jakobsson P, Jorfeldt L, Brundin A. Skeletal muscle metabolites and fiber types in patients with advanced

chronic obstructive pulmonary disease (COPD), with and without chronic respiratory failure Eur Respir J 1990;

3:192-196 [Context Link]

5 Whittom F, Jobin J, Simard P-M, et al. Histochemical and morphological characteristics of the vastus

lateralis muscle in COPD patients. Med Sci Sports Exerc 1998; 30:1467-1474 Request Permissions Buy Now

Bibliographic Links [Context Link]

6 Satta A, Migliori GB, Spanevello A, et al. Fiber types in skeletal muscles of chronic obstructive pulmonary

disease patients related to respiratory function and exercise tolerance. Eur Respir J 1997; 10:2853-2860

Bibliographic Links [Context Link]

7 Jobin J, Maltais F, Doyon JF, et al. Chronic obstructive pulmonary disease: capillarity and fiber-type

characteristics of skeletal muscle. J Cardiopulm Rehab 1998; 18:432-437 Request Permissions Buy Now

Bibliographic Links [Context Link]

http://ovidsp.tx.ovid.com/sp-2.3/ovidweb.cgi?&S=AOOCFPMCEKDDOPEAMCELMFOKBEPFAA00&Link+Set=S.sh.15.16.19.40|29|sl_10 (8 de 13)16/11/2009 20:39:25

Ovid: Skeletal Muscle Function in COPD*.

8 Jakobsson P, Jordfelt L, Henriksson J. Metabolic enzyme activity in the quadriceps femoris muscle in

patients with severe chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1995; 151:374-377

Bibliographic Links [Context Link]

9 Maltais F, Simard A-A, Simard C, et al. Oxidative capacity of the skeletal muscle and lactic acid kinetics

during exercise in normal subjects and in patients with COPD. Am J Respir Crit Care Med 1996; 153:288-293

Bibliographic Links [Context Link]

10 Schols AMWJ, Wouters EFM, Soeters PB, et al. Body composition by bioelectrical impedance analysis

compared to deuterium dilution and skinfold anthropometry in patients with chronic obstructive pulmonary

disease. Am J Clin Nutr 1991; 53:421-424 Bibliographic Links [Context Link]

11 Casaburi R, Patessio A, Ioli F, et al. Reductions in exercise lactic acidosis and `ventilation as a result of

exercise training in patients with obstructive lung disease. Am Rev Respir Dis 1991; 143:9-18 Bibliographic

Links [Context Link]

12 Payen JF, Wuyam B, Levy P, et al. Muscular metabolism during oxygen supplementation in patients with

chronic hypoxemia. Am Rev Respir Dis 1993; 147:592-598 Bibliographic Links [Context Link]

13 Maltais F, Jobin J, Sullivan MJ, et al. Lower limb metabolic and hemodynamic responses during exercise in

normal subjects and in COPD. J Appl Physiol 1998; 84:1573-1580 [Context Link]

14 Casaburi R, Storer TW, Wasserman K. Mediation of reduced ventilatory response to exercise after

endurance training. J Appl Physiol 1987; 63:1533-1538 Bibliographic Links [Context Link]

15 Gallager CG. Exercise limitation and clinical exercise testing in chronic obstructive pulmonary disease. Clin

Chest Med 1994; 15:305-326 [Context Link]

16 Nery LE, Wasserman K, Andrews JD, et al. Ventilatory and gas exchange kinetics during exercise in chronic

airways obstruction. J Appl Physiol 1982; 53:1594-1602 Bibliographic Links [Context Link]

17 Casaburi R, Porszasz J, Burns MR, et al. Physiologic benefits of exercise training in rehabilitation of severe

COPD patients. Am J Respir Crit Care Med 1997; 155:1541-1551 Bibliographic Links [Context Link]

http://ovidsp.tx.ovid.com/sp-2.3/ovidweb.cgi?&S=AOOCFPMCEKDDOPEAMCELMFOKBEPFAA00&Link+Set=S.sh.15.16.19.40|29|sl_10 (9 de 13)16/11/2009 20:39:25

Ovid: Skeletal Muscle Function in COPD*.

18 Casaburi R. Deconditioning. In: Fishman AP, ed. Pulmonary rehabilitation. New York, NY: Marcel Dekker,

1996; 213-230 [Context Link]

19 Mercier JR, Hokanson JF, Brooks GA. Effects of cyclosporin A on skeletal muscle mitochondrial respiration

and endurance times in rats. Am J Respir Crit Care Med 1995; 151:1848-1851 [Context Link]

20 Bloomfield SA. Changes in musculoskeletal structure and function with prolonged bed rest. Med Sci Sports

Exerc 1997; 29:197-206 Request Permissions Buy Now Bibliographic Links [Context Link]

21 Rochester DF. Nutritional repletion. Semin Respir Med 1992; 13:44-52 Bibliographic Links [Context Link]

22 Schols AM, Buurman WA, Staal van den Brekel, et al. Evidence for a relation between metabolic

derangements and increased levels of inflammatory mediators in a subgroup of patients with chronic

obstructive pulmonary disease. Thorax 1996; 51:819-824 [Context Link]

23 LeRoith D, Adama M, Werner H, et al. Insulin-like growth factors and their receptors as growth regulators

in normal physiology and pathologic states. Trends Endocrinol Metab 1991; 2:134-139 [Context Link]

24 Sinha-Hikim I, Arver S, Beall G, et al. The use of a sensitive equilibrium dialysis method for the

measurement of free testosterone levels in healthy, cycling women and in human immunodeficiency virus-

infected women. J Clin Endocrinol Metab 1998; 83:1312-1318 Bibliographic Links [Context Link]

25 Davis SR, Burger HG. The rationale for physiological testosterone replacement in women. Bailliere's Clin

Endrocrinol Metab 1998; 12:391-405 [Context Link]

26 Davidson JM, Chen JJ, Crapo L, et al. Hormonal changes and sexual function in aging men. J Clin

Endrocrinol Metab 1983; 57:71-77 [Context Link]

27 Rudman D, Mattson DE, Nagraj HS. Plasma testosterone in nursing home men. J Clin Epidemiol 1988;

41:231-236 Bibliographic Links [Context Link]

28 Casaburi R, Goren S, Bhasin S. Substantial prevalence of low anabolic hormone levels in COPD patients

undergoing rehabilitation [abstract]. Am J Respir Crit Care Med 1996; 153:A128 [Context Link]

29 Semple D'AP, Beastall GH, Watson WS, et al. Serum testosterone depression associated with hypoxia in

respiratory failure. Clin Sci 1980; 58:105-106 [Context Link]

http://ovidsp.tx.ovid.com/sp-2.3/ovidweb.cgi?&S=AOOCFPMCEKDDOPEAMCELMFOKBEPFAA00&Link+Set=S.sh.15.16.19.40|29|sl_10 (10 de 13)16/11/2009 20:39:25

Ovid: Skeletal Muscle Function in COPD*.

30 Shee CD. Risk factors for hydrocortisone myopathy in acute severe asthma. Respir Med 1990; 84:229-233

Bibliographic Links [Context Link]

31 DeCramer M, deBock V, Dom R. Functional and histologic picture of steroid-induced myopathy in chronic

obstructive pulmonary disease. Am J Respir Crit Care Med 1996; 153:1958-1964 [Context Link]

32 Fiaccadori E, Coffrini E, Fracchia C, et al. Hypophosphatemia and phosphorus depletion in respiratory and

peripheral muscles of patients with respiratory failure due to COPD. Chest 1994; 105:1392-1398 Bibliographic

Links [Context Link]

33 Sullivan MJ, Green HJ, Cobb FR. Skeletal muscle biochemistry and histology in ambulatory patients with

long-term heart failure. Circulation 1990; 81:518-527 Ovid Full Text Bibliographic Links [Context Link]

34 Maltais F, Leblanc P, Simard C, et al. Skeletal muscle adaptation to endurance training in patients with

chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1996; 154:442-447 Bibliographic Links

[Context Link]

35 Mohsenifar Z, Horak D, Brown HV, et al. Sensitive indices of improvement in a pulmonary rehabilitation

program. Chest 1983; 83:189-192 Bibliographic Links [Context Link]

36 Vallet G, Ahmaidi S, Serres I, et al. Comparison of two training programmes in chronic airway limitation

patients: standardized versus individualized protocols. Eur Respir J 1997; 10:114-122 Bibliographic Links

[Context Link]

37 Casaburi R. Special considerations for exercise training in chronic lung disease. In: ACSM resource manual:

guidelines for exercise testing and prescription. 3rd ed. Baltimore, MD: Williams and Wilkins, 1998; 334-338

[Context Link]

38 American College of Sports Medicine Position Stand. The recommended quantity and quality of exercise for

developing and maintaining cardiorespiratory and muscular fitness in healthy adults. Med Sci Sports Exerc

1998; 30:975-991 [Context Link]

39 Punzal PA, Ries AL, Kaplan RM, et al. Maximum intensity exercise training in patients with chronic

obstructive pulmonary disease. Chest 1991; 100:618-623 Bibliographic Links [Context Link]

http://ovidsp.tx.ovid.com/sp-2.3/ovidweb.cgi?&S=AOOCFPMCEKDDOPEAMCELMFOKBEPFAA00&Link+Set=S.sh.15.16.19.40|29|sl_10 (11 de 13)16/11/2009 20:39:25

Ovid: Skeletal Muscle Function in COPD*.

40 Sipilä S, Suominen H. Effects of strength and endurance training on thigh and leg muscle mass and

composition in elderly women. J Appl Physiol 1995; 75:334-340 [Context Link]

41 Gosselink R, Troosters T, Decramer M. Peripheral muscle weakness contributes to exercise limitation in

COPD. Am J Respir Crit Care Med 1996; 153:976-980 Bibliographic Links [Context Link]

42 Bernard S, Leblanc P, Whittom F, et al. Peripheral muscle weakness in patients with chronic obstructive

pulmonary disease. Am J Respir Crit Care Med 1998; 158:629-634 Bibliographic Links [Context Link]

43 Cuneo RC, Salomon F, Wiles CM, et al. Growth hormone treatment in growth hormone-deficient adults: I.

Effects on muscle mass and strength. J Appl Physiol 1991; 70:688-694 Bibliographic Links [Context Link]

44 Papadakis MA, Grady D, Black D, et al. Growth hormone replacement in healthy older men improves body

composition but not functional ability. Ann Intern Med 1996; 124:708-716 [Context Link]

45 Schambelan M, Mulligan K, Grunfeld C, et al. Recombinant human growth hormone in patients with HIV-

associated wasting. Ann Intern Med 1996; 125:873-882 Ovid Full Text Bibliographic Links [Context Link]

46 Burdet L, deMuralt B, Schultz Y, et al. Administration of growth hormone to underweight patients with

chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1997; 156:1800-1806 [Context Link]

47 Mantzoros CS, Moses AL. Whither recombinant human growth hormone? Ann Intern Med 1996; 125:932-934

Ovid Full Text Bibliographic Links [Context Link]

48 Bhasin S, Storer TW, Berman N, et al. Testosterone replacement increases fat-free mass and muscle size in

hypogonadal men. J Clin Endrocrinol Metab 1997; 82:407-413 [Context Link]

49 Casaburi R, Storer TW, Bhasin S. Testosterone effects on body composition and muscle performance. In:

Bhasin S, Gabelnick H, Spieler J, et al, eds. Androgens: biology, pharmacology and clinical applications, New

York, NY: Wiley Liss, 1996; 283-288 [Context Link]

50 Bhasin S, Storer TW, Berman N, et al. The effects of supraphysiological doses of testosterone on muscle

size and strength in normal men. N Engl J Med 1996; 335:1-7 [Context Link]

51 Grinspoon S, Corcoran C, Askari H, et al. Effects of androgen administration in men with the AIDS wasting

syndrome. Ann Intern Med 1998; 129:18-26 Ovid Full Text Bibliographic Links [Context Link]

http://ovidsp.tx.ovid.com/sp-2.3/ovidweb.cgi?&S=AOOCFPMCEKDDOPEAMCELMFOKBEPFAA00&Link+Set=S.sh.15.16.19.40|29|sl_10 (12 de 13)16/11/2009 20:39:25

Ovid: Skeletal Muscle Function in COPD*.

52 Schols AM, Soeters PB, Mostert R, et al. Physiologic effects of nutritional support and anabolic steroids in

patients with chronic obstructive pulmonary disease: a placebo controlled randomized trial. Am J Respir Crit

Care Med 1995; 152:1268-1274 Bibliographic Links [Context Link]

53 Ferriera EM, Verreschi IT, Nery LE, et al. The influence of 6 months of oral anabolic steroids on body mass

and respiratory muscles in undernourished COPD patients. Chest 1998; 114:19-28 [Context Link]

54 Bagatell CJ, Bremner WJ. Androgens in men: uses and abuses. N Engl J Med 1996; 334:707-714 Ovid Full

Text Bibliographic Links [Context Link]

55 Rolf C, Nieschlag E. Potential adverse effects of long-term testosterone therapy. Bailliere's Clin Endocrinol

Metab 1998; 12:521-534 [Context Link]

56 Brinka PJ, Jochen AL, Cuisinier M, et al. Polycythemia as a complication of testosterone replacement

therapy in nursing home men with low testosterone levels. J Am Geriatric Soc 1995; 43:899-901 [Context Link]

Key words: anabolic; COPD; exercise; growth hormone; muscle; strength; testosterone

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