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Therapies of muscle dysfunction in obstructive lung disease

Institution: LA Biomedical Research Institute at Harbor-UCLA Medical Center
Investigator(s): Richard Casaburi, M.D., Ph.D.
Award Cycle: 1997 (Cycle 6) Grant #: 6RT-0362 Award: $659,714
Subject Area: Pulmonary Disease
Award Type: Research Project Awards
Abstracts

Initial Award Abstract
This project aims to improve the effectiveness of medical treatment for people with lung disease produced by cigarette smoking. Chronic obstructive pulmonary disease (COPD, which includes emphysema and bronchitis) is a disorder affecting approximately 14 million people in the United States. It is a disabling disease and inability to exercise is usually the foremost problem. It is becoming clear that these patients suffer not only from poorly functioning lungs but from poorly functioning muscles as well. We will focus on strategies that can be predicted to improve the muscle's ability to tolerate exercise. Two specific strategies will be explored. First, in men, the naturally occurring body chemical, testosterone, is important in maintaining muscle mass. We have found that men with COPD have low levels of this chemical. We will determine whether administering testosterone to male COPD patients will increase muscle mass (and exercise tolerance) as we have demonstrated in healthy elderly men. Second, we have found that patients with COPD usually have a low level of physical activity; we will determine whether a conditioning program consisting of a varied group of weight lifting exercises improves exercise tolerance.

We will randomly assign 48 men with COPD to one of four groups that will receive one of the following treatments: no exercise training and no testosterone, exercise training (for one hour a day three times per week) but no testosterone, testosterone but no exercise training, or both exercise training and testosterone. A number of state-of-the art measurements will be made before and after the 10 week study period including: 1 ) precise measurement of the muscle and fat mass of the body, 2) muscle strength by weight lifting and by measuring the electrical activity of the muscle, 3) exercise capacity measured on a stationary bicycle, 4) strength of the breathing muscles and 5) the overall quality of life, assessed by well-designed questionnaires. Also a sophisticated x-ray procedure will be used to measure the mass of the heart and the strength of the heart muscle both at rest and during exercise. In this way, we will determine whether heart muscle function (which is often a problem in these patients) is improved. In this study, a number of safeguards will be in place to assure the participants' safety. Programs are already in place to help rehabilitate patients with COPD. This study should be directly applicable to these programs and help to decrease the suffering of patients with this smoking-related disease.

Final Report
It was the aim of this project to improve the effectiveness of treatment for people with lung disease produced by cigarette smoking. Chronic obstructive pulmonary disease (COPD, also called emphysema or bronchitis) afflicts approximately 14 million people in the United States. It is a disabling disorder and inability to exercise is usually the foremost problem. It is now clear that these patients suffer not only from poor lung function but from poor muscle function as well. We focused on strategies intended to improve the muscle's ability to tolerate exercise. Two strategies were explored. First, in men the naturally occurring body chemical, testosterone, is important in maintaining muscle mass. Many men with COPD have low testosterone levels. We determined whether administering testosterone to COPD patients increases muscle mass and strength as we have demonstrated in healthy young men. Second, we determined whether a conditioning program consisting of a group of weight lifting exercises improves muscle strength.

We recruited a total of 52 men with COPD; 47 completed the protocol. They were assigned by chance to one of four groups that received: no strength training and no testosterone, strength training (for one hour a day three times per week) but no testosterone, testosterone (100mg of testosterone enanthate intramuscularly) but no strength training, or both strength training and testosterone. A large number of state-of-the art measurements were made before and after the 10 week study period. On average, subjects had severe COPD (FEV1=40% predicted); measures of pulmonary function did not change in any group. Testosterone levels on entry were low; subjects receiving testosterone doubled nadir blood levels to the middle of the normal range for young men. In the groups receiving testosterone, muscle mass (assessed by DEXA scan) increased; in the group receiving strength training alone muscle mass of the legs increased. The group receiving the combined intervention had a 3.3kg (6.3%) increase in muscle mass and an average decrease in fat mass of 1.5kg (6%). Strength of the thigh muscles (measured by 1 repetition maximum of the leg press exercise) increased both in the groups receiving testosterone alone and strength training alone; the group receiving the combined intervention experienced an average 23.3% increase in strength. As expected, measures of exercise endurance did not improve. We employed an x-ray procedure capable of measuring cardiac dimensions and contractility and found that the groups receiving testosterone supplementation increased left ventricular wall mass (by an average of approximately 5%). There were no adverse effects of these interventions; specifically no hepatic or prostatic side-effects were observed. A companion study funded by TRDRP is studying the changes in muscle tissue structure (determined by muscle biopsy) produced by these interventions.

These findings suggest that both strength training and testosterone supplementation will be beneficial additions to programs of pulmonary rehabilitation for patients with COPD and, thereby, help decrease the suffering of patients with this smoking-related disease.
Publications

Physiologic benefits of exercise training in rehabilitation of severe COPD patients
Periodical: American Journal of Respiratory and Critical Care Medicine Index Medicus:
Authors: Casaburi RJ, Porszasz MR, Burns ER, Carithers RSY,Chang, Cooper CB ART
Yr: 1997 Vol: 155 Nbr: Abs: Pg: 1541-1551

Replacement doses of testosterone increase fat-free mass and muscle size in hypogonadal men
Periodical: Journal of Clincal Endocrinology and Metabolism Index Medicus:
Authors: Bhasin S, Storer TW, Berman N, et al ART
Yr: 1997 Vol: 82 Nbr: Abs: Pg: 407-413

Effect of acute bicarbonate administration on the responses to incremental exercise responses of COPD patients
Periodical: Medicine and Science in Sports and Exercise Index Medicus:
Authors: Coppoolse R, Barstow TJ, Stringer WW, Carithers E, Casaburi R ART
Yr: 1997 Vol: 29 Nbr: Abs: Pg: 725-732

The effect of exercise training on aerobic fitness, immune function, and quality of life in HIV+ patients
Periodical: Medicine and Science in Sports and Exercise Index Medicus:
Authors: Stringer WW, Berezovskaya M, O'Brien WA, Beck CK, Casaburi R ART
Yr: 1998 Vol: 30 Nbr: Abs: Pg: 11-16

Clinical exercise testing with reference to lung disease: indications, standardization and interpretation strategies
Periodical: European Respiratory Journal Index Medicus:
Authors: Roca J, Whipp BJ, Austi AGN, et al ART
Yr: 1997 Vol: 10 Nbr: Abs: Pg: 2662-2689

Equipment, measurements and quality control in clinical exercise testing
Periodical: European Respiratory Monthly Index Medicus:
Authors: Casaburi R, Cotes JE, Prefaut C ART
Yr: 1997 Vol: 6 Nbr: Abs: Pg: 72-87

Exercise training in chronic lung disease: exercise prescription
Periodical: European Respiratory Monthly Index Medicus:
Authors: Patessio A, Casaburi R, Prefaut C, Folgering H ART
Yr: 1997 Vol: 6 Nbr: Abs: Pg: 129-146

Pulmonary rehabilitation: evidence based guidelines
Periodical: Chest Index Medicus:
Authors: Ries AL, Carlin V, Carrieri-Kohlman R, et al ART
Yr: 1997 Vol: 112 Nbr: Abs: Pg: 1363-1396

Anabolic therapies in chronic obstructive pulmonary disease
Periodical: Monaldi Archives of Chest Disease Index Medicus:
Authors: Casaburi R ART
Yr: 1998 Vol: 53 Nbr: Abs: Pg: 454-459

Rationale for anabolic therapy to facilitate rehabilitation in chronic obstructive pulmonary disease
Periodical: Bailliere's Clinical Endocrinology and Metabolism Index Medicus:
Authors: Casaburi R ART
Yr: 1998 Vol: 12 Nbr: 3 Abs: Pg: 407-418

Emerging issues in androgen replacement therapy
Periodical: Journal of Clincal Endocrinology and Metabolism Index Medicus:
Authors: Bhasin S, Bremner WJ ART
Yr: 1997 Vol: 82 Nbr: 1 Abs: Pg: 3-7

The use of a sensitive equilibrium dialysis assay for measurements of free testosterone levels during the normal menstrual cycle and in HIV-infected women
Periodical: Journal of Clincal Endocrinology and Metabolism Index Medicus:
Authors: Sinha-Hikim I, Arver S, Beall G, et al ART
Yr: 1998 Vol: 83 Nbr: Abs: Pg: 1101-1117

Effects of testosterone replacement with a non-genital system, Androderm, in HIV-infected men with low testosterone levels
Periodical: Journal of Clincal Endocrinology and Metabolism Index Medicus:
Authors: Bhasin S, Storer TW, Asbel-Sethi N, et al ART
Yr: 0 Vol: 83 Nbr: Abs: Pg: 3155-3162

Age-associated sarcopenia: Issies in testosterone replacement of older men
Periodical: Journal of Clincal Endocrinology and Metabolism Index Medicus:
Authors: Bhasin S, Tenover JS ART
Yr: 1997 Vol: 82 Nbr: Abs: Pg: 1659-1661

Electron beam tomography of the coronary arteries:Relationship of coronary calcium score to arteriographic findings in asymptomatic and symptomatic adults
Periodical: American Journal of Cardiology Index Medicus:
Authors: Buerci AD, Spadaro LA, Popma JJ, et al ART
Yr: 1997 Vol: 79 Nbr: Abs: Pg: 128-133

Coronary calcium and standard risk factors in symptomatic patients referred for coronary angiography
Periodical: American Heart Journal Index Medicus:
Authors: Kennedy JM, Shavelle RM, Wong SM, Budoff MJ, Detrano RC ART
Yr: 1998 Vol: 135 Nbr: Abs: Pg: 696-702

Comparison of ultra fast computed tomography and sestamibi in the evaluation of coronary artery disease
Periodical: American Journal of Cardiology Index Medicus:
Authors: Budoff MJ, Georgiou D, Narahara KA, French WJ, Mena, I, Brundage BH ART
Yr: 1998 Vol: 81 Nbr: Abs: Pg: 682-687

Clinical utility of electron beam computed tomography
Periodical: Medical Progress Index Medicus:
Authors: Budoff MJ ART
Yr: 1998 Vol: Nbr: Abs: Pg:

Randomized placebo controlled study of growth hormone in severe COPD patients undergoing endurance exercising training.
Periodical: American Journal of Respiratory and Critical Care Medicine Index Medicus:
Authors: Casaburi R, Carithers E, Tosolini J, Phillips J, Bhasin, S ABS
Yr: 1997 Vol: 155 Nbr: 4 Abs: Pg: A498

Effects of physiologic testosterone replacement by Androderm, a non-genital transdermal testosterone system, in HIV-infected men with low testosterone levels
Periodical: Proceedings of the Endocrine Society Meeting Index Medicus:
Authors: Bhasin S, Storer TW, Berman N, et al ABS
Yr: 1998 Vol: Nbr: Abs: Pg:

cDNA cloning, chromosomal mapping, mRNA expression, and secretion of myostatin, a muscle growth inhibitor
Periodical: Proceedings of the Endocrine Society Meeting Index Medicus:
Authors: Gonzalez-Cadavid N, Taylor WE, Ma K, et al ABS
Yr: 1998 Vol: Nbr: Abs: Pg:

Exercise testing and electron beam computed tomography in the evaluation of coronary artery disease
Periodical: Circulation Index Medicus:
Authors: Shavelle DM, Budoff MJ, Lamont DH, Shavelle RM, Kennedy JM, Brundage BH ABS
Yr: 1997 Vol: 96 Nbr: 8 Abs: Pg: 1-306

Intravenous three dimensional coronary angiography using contrast enhanced electron beam computed tomography
Periodical: Journal of the American College of Cardiology Index Medicus:
Authors: Budoff MJ, Oudiz RJ, Zalace CP, et al ABS
Yr: 1997 Vol: 29 Nbr: 2 Abs: Pg: 393-A

Coronary calcium scanning identifies patients with false positive stress tests
Periodical: Circulation Index Medicus:
Authors: Lamont DH, Budoff MJ, Shavelle DM, Brundage BH, Hagar JM ABS
Yr: 1997 Vol: 96 Nbr: 8 Abs: Pg: 1-306

Effects of cigarette-smoking levels of carbon monoxide on carboxyhemoglobin, exercise gas exchange and hemodynamics
Periodical: American Journal of Respiratory and Critical Care Medicine Index Medicus:
Authors: Lewis DA, Otsuka T, Hansen JE, Wasserman K ABS
Yr: 1998 Vol: 157 Nbr: 4, part 2 Abs: Pg: A94

Changes in arterial blood gases during obstructive sleep apnea
Periodical: American Journal of Respiratory and Critical Care Medicine Index Medicus:
Authors: Abe J, Kawaoka J, Lewis DA ABS
Yr: 1998 Vol: 157 Nbr: 4, part 2 Abs: Pg: A58

Mechanism of the acute ventilatory increase to pulse inhalation of carbon monoxide during exercise
Periodical: FASEB Journal Index Medicus:
Authors: Lewis DA, Otsuka T, Hansen JE, Wasserman K ABS
Yr: 1998 Vol: 12 Nbr: 4, part 1 Abs: Pg: A498

Pharmacologic modulators of respiratory control
Periodical: Monaldi Archives of Chest Disease Index Medicus:
Authors: Casaburi R ART
Yr: 1198 Vol: 53 Nbr: Abs: Pg: 287-293

The human myostatin gene: genomic organization, chromosomal mapping, cDNA expression, and secretion in healthy and HIV-infected men
Periodical: Proceedings of the National Academy of Sciences of the United States of America Index Medicus:
Authors: ART
Yr: 1998 Vol: 95 Nbr: Abs: Pg: 14938-14943

Effect of muscle fibre type and cardiorespiratory fitness on the oxygen uptake/work rate slope during incremental exercise
Periodical: Journal of Physiology Index Medicus:
Authors: Jones AM, Barstow TJ, Nguyen PH, Casaburi R ABS
Yr: 1998 Vol: Nbr: Abs: 9P Pg: 511

The spirometric efficacy of once daily dosing with tiotropium in stable COPD
Periodical: American Journal of Respiratory and Critical Care Medicine Index Medicus:
Authors: Casaburi R, Serby CW, Menjoge SS, Witek TJ ABS
Yr: 1999 Vol: 159 Nbr: 3 Abs: A524 Pg:

Skeletal muscle dysfunction in obstructive pulmonary disease
Periodical: American Journal of Respiratory and Critical Care Medicine Index Medicus:
Authors: Casaburi R, Gosselink M, Decramer PNR, et al ART
Yr: 1999 Vol: 159 Nbr: 4 part 2 Abs: Pg: S1-S40

Skeletal muscle function in COPD
Periodical: Chest Index Medicus:
Authors: Casaburi R ART
Yr: 2000 Vol: 117 Nbr: Abs: Pg: 267S-271S

Comparison of effects of supervised versus self-monitored training programmes in patients with chronic obstructive pulmonary disease
Periodical: European Respiratory Journal Index Medicus:
Authors: Puente-Maestu L, Sanz ML, Sanz P, Cubillo JM, Mayol J, Casaburi R ART
Yr: 2000 Vol: 15 Nbr: Abs: Pg: 517-526

Influence of muscle fibre type and fitness on the oxygen uptake/power slope during incremental exercise in humans
Periodical: Experimental Physiology_x000D_ Index Medicus:
Authors: Barstow TJ, Jones AM, Nguyen PH, Casaburi R ART
Yr: 2000 Vol: 85 Nbr: Abs: Pg: 109-116

The spirometric efficacy of once daily dosing with tiotropium in stable COPD
Periodical: Chest Index Medicus:
Authors: Casaburi R, Briggs DD, Donohue JF, Serby CW, Menjoge SS, Witek TJ ART
Yr: 0 Vol: Nbr: Abs: Pg:

Effects of the workrate incremental rate on the response to exercise in patients with COPD
Periodical: Medicine and Science in Sports and Exercise Index Medicus:
Authors: Debigare R, Maltais F, Mallet M, Casaburi R ART
Yr: 2000 Vol: 32 Nbr: Abs: Pg: 1365-1368

New advances in anticholinergic therapy - clinical effectiveness of a very long-acting anticholinergic, tiotropium promide, for inhalation once-daily in COPD
Periodical: Lungeforum Index Medicus:
Authors: Casaburi R, Serby CW, Menjoge SS, Witek T ABS
Yr: 1999 Vol: 9 Nbr: 11 Abs: 12 Pg:

Comparison of two pulse 02 delivery modes vs continuous flow 02 during exe5rcise in hypoxemic COPD patients
Periodical: American Journal of Respiratory and Critical Care Medicine Index Medicus:
Authors: Porszasz J, Ditch J, Bradley R, Casaburi R ABS
Yr: 2000 Vol: 161 Nbr: 3 Abs: A227 Pg:

Androgen effects on body composition and muscle function: implications for the use of androgens as anabolic agents in sarcopenic states
Periodical: Bailliere's Clinical Endocrinology and Metabolism Index Medicus:
Authors: Bross R, Casaburi R, Storer TW, Bhasin S ART
Yr: 1998 Vol: 12 Nbr: 3 Abs: Pg: 365-378

Peripheral muscle dysfunction in chronic obstructive pulmonary disease
Periodical: Clinics in Chest Medicine Index Medicus:
Authors: Maltais F, LeBlanc P, Jobin J, Casaburi R ART
Yr: 2000 Vol: 21 Nbr: 4 Abs: Pg: 665-677

Exercise limitation in COPD: Role of skeletal muscle dysfunction
Periodical: Medicine and Science in Sports and Exercise Index Medicus:
Authors: Casaburi R ART
Yr: 2001 Vol: Nbr: Abs: Pg:

Effect of oxygen on hyperinflation and exercise endurance in non-hypoxemic COPD patients
Periodical: European Respiratory Journal Index Medicus:
Authors: Somfay A, Porszasz J, Lee SM, Casaburi R ART
Yr: 0 Vol: Nbr: Abs: Pg:

Testosterone dose-response relationships in healthy young men
Periodical: American Journal of Physiology Index Medicus:
Authors: Bhasin S, Woodhouse L, Casaburi R, et al ART
Yr: 0 Vol: Nbr: Abs: Pg:

Resistance training, but not testosterone supplementation, increases thigh muscle specific tension in men
Periodical: Proceedings of the Western American Federation of Medical Research Index Medicus:
Authors: Storer TW, Casaburi R, Singh AB, et al ABS
Yr: 0 Vol: Nbr: Abs: Pg:

Testosterone dose response relationships in healthy young men
Periodical: Proceedings of the Western American Federation of Medical Research Index Medicus:
Authors: Storer TW, Casaburi R, Singh AB, et al ABS
Yr: 0 Vol: Nbr: Abs: Pg:

Megestrol acetate induces weight gain and stimulates ventilation in underweight COPD patients: a randomized, double-blind, placebo-controlled, multi-center trial
Periodical: American Journal of Respiratory and Critical Care Medicine Index Medicus:
Authors: Weisberg J, Casaburi R, Olson J, Wanger J ABS
Yr: 2001 Vol: 163 Nbr: 5 Abs: A503 Pg:

Comparison of a new linearized treadmill ramp protocol with a cycle ergometer ramp protocol in cardiopulmonary exercise testing (CPX)
Periodical: American Journal of Respiratory and Critical Care Medicine Index Medicus:
Authors: Porszasz J, Woodhouse L, Somfay A, Yu A, DeBellis E, Casaburi R ABS
Yr: 2001 Vol: 163 Nbr: 5 Abs: A267 Pg:

Effect of supplemental oxygen on hyperinflation and exercise endurance in non-hypoxemic COPD patients
Periodical: American Journal of Respiratory and Critical Care Medicine Index Medicus:
Authors: Somfay A, Porszasz J, Lee SM, Casaburi R ABS
Yr: 2001 Vol: 163 Nbr: 5 Abs: Pg:

Testosterone dose-dependently increases muscle strength, power and endurance, but not measures of aerobic capacity in healthy young men
Periodical: Proceedings of the American College of Sports Medicine Index Medicus:
Authors: Storer TW, Magliano L, Woodhouse J, Dzekov J, Casaburi R, Bhasin S ABS
Yr: 0 Vol: Nbr: Abs: Pg:

Testosterone dose-response relationships differ among androgen-dependent biochemical and physiological processes in healthy young men
Periodical: Proceedings of the Endocrine Society Meeting Index Medicus:
Authors: Woodhouse L, Storer TW, Casaburi R, et al ABS
Yr: 2001 Vol: Nbr: Abs: Pg: P2-476

Dose-dependent effects of testosterone on muscle strength, power and fatigability in healthy young men
Periodical: Proceedings of the Endocrine Society Meeting Index Medicus:
Authors: Storer TW, Woodhouse LJ, Casaburi R, et al ABS
Yr: 2001 Vol: Nbr: Abs: OR11-1 Pg:

Testosterone-induced increase in muscle size in healthy men is associated with muscle fiber hypertrophy, but not fiber hyperplasia
Periodical: Proceedings of the Endocrine Society Meeting Index Medicus:
Authors: Sinha-Hikim I, Woodhouse LJ, Shen R, et al ABS
Yr: 2001 Vol: Nbr: Abs: OR11-2 Pg: