Therapies of muscle dysfunction in obstructive lung disease

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


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.
 
 
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  Yr: 1997 Vol: 155 Nbr: Abs: Pg:1541-1551
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Periodical:Bailliere's Clinical Endocrinology and Metabolism Index Medicus: Baillieres Clin Endocrinol Metab
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  Yr: 1998 Vol: 12 Nbr: 3 Abs: Pg:365-378
Comparison of effects of supervised versus self-monitored training programmes in patients with chronic obstructive pulmonary disease
Periodical:European Respiratory Journal Index Medicus: Eur Respir J
  Authors: Puente-Maestu L, Sanz ML, Sanz P, Cubillo JM, Mayol J, Casaburi R
  Yr: 2000 Vol: 15 Nbr: Abs: Pg:517-526
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:
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  Yr: 2001 Vol: Nbr: Abs: Pg:P2-476
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: Am J Respir Crit Care Med
  Authors: Porszasz J, Ditch J, Bradley R, Casaburi R
  Yr: 2000 Vol: 161 Nbr: 3 Abs: A227 Pg:
Effect of muscle fibre type and cardiorespiratory fitness on the oxygen uptake/work rate slope during incremental exercise
Periodical:Journal of Physiology Index Medicus: J Physio (Lond)
  Authors: Jones AM, Barstow TJ, Nguyen PH, Casaburi R
  Yr: 1998 Vol: Nbr: Abs: 9P Pg:511
Changes in arterial blood gases during obstructive sleep apnea
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  Yr: 1998 Vol: 157 Nbr: 4, part 2 Abs: Pg:A58
Influence of muscle fibre type and fitness on the oxygen uptake/power slope during incremental exercise in humans
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  Authors: Barstow TJ, Jones AM, Nguyen PH, Casaburi R
  Yr: 2000 Vol: 85 Nbr: Abs: Pg:109-116
Replacement doses of testosterone increase fat-free mass and muscle size in hypogonadal men
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Exercise testing and electron beam computed tomography in the evaluation of coronary artery disease
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  Authors: Shavelle DM, Budoff MJ, Lamont DH, Shavelle RM, Kennedy JM, Brundage BH
  Yr: 1997 Vol: 96 Nbr: 8 Abs: Pg:1-306
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
  Yr: 1999 Vol: 9 Nbr: 11 Abs: 12 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: Am J Respir Crit Care Med
  Authors: Casaburi R, Carithers E, Tosolini J, Phillips J, Bhasin, S
  Yr: 1997 Vol: 155 Nbr: 4 Abs: Pg:A498
The use of a sensitive equilibrium dialysis assay for measurements of free testosterone levels during the normal menstrual cycle and in HIV-infected women
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  Authors: Sinha-Hikim I, Arver S, Beall G, et al
  Yr: 1998 Vol: 83 Nbr: Abs: Pg:1101-1117
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
  Yr: 2001 Vol: Nbr: Abs: OR11-2 Pg:
Equipment, measurements and quality control in clinical exercise testing
Periodical:European Respiratory Monthly Index Medicus: Eur Respir Mon
  Authors: Casaburi R, Cotes JE, Prefaut C
  Yr: 1997 Vol: 6 Nbr: Abs: Pg:72-87
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
  Yr: 2001 Vol: Nbr: Abs: OR11-1 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: Am J Respir Crit Care Med
  Authors: Somfay A, Porszasz J, Lee SM, Casaburi R
  Yr: 2001 Vol: 163 Nbr: 5 Abs: Pg:
Skeletal muscle dysfunction in obstructive pulmonary disease
Periodical:American Journal of Respiratory and Critical Care Medicine Index Medicus: Am J Respir Crit Care Med
  Authors: Casaburi R, Gosselink M, Decramer PNR, et al
  Yr: 1999 Vol: 159 Nbr: 4 part 2 Abs: Pg:S1-S40
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: Am J Respir Crit Care Med
  Authors: Lewis DA, Otsuka T, Hansen JE, Wasserman K
  Yr: 1998 Vol: 157 Nbr: 4, part 2 Abs: Pg:A94
The spirometric efficacy of once daily dosing with tiotropium in stable COPD
Periodical:American Journal of Respiratory and Critical Care Medicine Index Medicus: Am J Respir Crit Care Med
  Authors: Casaburi R, Serby CW, Menjoge SS, Witek TJ
  Yr: 1999 Vol: 159 Nbr: 3 Abs: A524 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: Med Sci Sports Exerc
  Authors: Debigare R, Maltais F, Mallet M, Casaburi R
  Yr: 2000 Vol: 32 Nbr: Abs: Pg:1365-1368
Skeletal muscle function in COPD
Periodical:Chest Index Medicus: Chest
  Authors: Casaburi R
  Yr: 2000 Vol: 117 Nbr: Abs: Pg:267S-271S
Comparison of ultra fast computed tomography and sestamibi in the evaluation of coronary artery disease
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Effects of testosterone replacement with a non-genital system, Androderm, in HIV-infected men with low testosterone levels
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Exercise training in chronic lung disease: exercise prescription
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Peripheral muscle dysfunction in chronic obstructive pulmonary disease
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Clinical exercise testing with reference to lung disease: indications, standardization and interpretation strategies
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Coronary calcium scanning identifies patients with false positive stress tests
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  Authors: Stringer WW, Berezovskaya M, O'Brien WA, Beck CK, Casaburi R
  Yr: 1998 Vol: 30 Nbr: Abs: Pg:11-16
Intravenous three dimensional coronary angiography using contrast enhanced electron beam computed tomography
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Effect of acute bicarbonate administration on the responses to incremental exercise responses of COPD patients
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  Authors: Coppoolse R, Barstow TJ, Stringer WW, Carithers E, Casaburi R
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Emerging issues in androgen replacement therapy
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