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Anabolic therapies for muscle dysfunction in women with COPD

Institution: LA Biomedical Research Institute at Harbor-UCLA Medical Center
Investigator(s): Richard Casaburi, M.D., Ph.D.
Award Cycle: 2001 (Cycle 10) Grant #: 10RT-0046 Award: $632,153
Subject Area: Pulmonary Disease
Award Type: Research Project Awards
Abstracts

Initial Award Abstract
This project aims to improve the effectiveness of medical treatment for women with lung disease produced by cigarette smoking. Chronic obstructive pulmonary disease (COPD, also called emphysema or bronchitis) is a disorder affecting approximately 14 million people in the United States. It is a disabling disorder and inability to exercise is usually the foremost problem. It is becoming clear that these patients suffer not only from poorly functioning lungs but also because the muscles of ambulation perform poorly. We have recently shown that muscle function can be improved in men with COPD both by strength training and by giving supplemental testosterone, a drug known to build muscles. Until now, most research into methods to improve muscle function has involved only men. However, the number of women suffering from COPD is accelerating and is nearly equal to that of men. The body chemicals that stimulate muscle growth operate differently in women than they do in men. We will focus on two specific strategies intended to improve the muscle's ability to tolerate exercise. First, there is a growing realization that testosterone is not only a “male hormone”. Though levels in women are much lower than in men, studies in healthy women suggest that testosterone supplementation increases muscle size. We have found that women with COPD have low levels of this chemical. However, the amount of testosterone that best balances the benefits of testosterone without creating troubling side effects has yet to be determined. We will determine whether administering testosterone to women with COPD will increase muscle mass and exercise tolerance. Second, we have found that women with COPD usually have a low level of activity; we will determine whether a strength conditioning program consisting of a varied group of exercises improves exercise tolerance.

We will assign by chance 72 women with COPD to one of six groups. Four of the groups will receive no training, but will apply a gel to their skin daily that will contain no testosterone or one of three doses of testosterone. Two of the groups will receive strength training (for one hour a day three times per week) plus either a gel with no testosterone or with the highest of the three doses of 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 in 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. 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 will help to decrease the suffering of patients with this smoking-related disease.
Publications

Skeletal muscle dysfunction in chronic obstructive pulmonary disease.
Periodical: Medicine and Science in Sports and Exercise Index Medicus:
Authors: Casaburi R ART
Yr: 2001 Vol: 33 Nbr: 7 Abs: Pg: S662 - S670

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, and Casaburi R ART
Yr: 2001 Vol: 18 Nbr: Abs: Pg: 77 - 84

Testosterone dose-response relationships in healthy young men.
Periodical: American Journal of Physiology Endocrinology and Metabolism Index Medicus:
Authors: Bhasin S, Woodhouse L, Casaburi R, Singh AB, Bhasin D, Berman N, Magliano L, et al ART
Yr: 2001 Vol: 281 Nbr: Abs: Pg: E1172 - E1181

21st century perspective on chronic obstructive pulmonary disease.
Periodical: Respiration Index Medicus:
Authors: Ward SA, and Casaburi R ART
Yr: 2001 Vol: 68 Nbr: Abs: Pg: 557 - 561

Megesterol acetate stimulates weight gain and ventilation in underweight COPD patients.
Periodical: Chest Index Medicus:
Authors: Weisberg J, Wanger J, Olson J, Streit B, Fogarty C, Martin T, and Casaburi R ART
Yr: 2002 Vol: 121 Nbr: Abs: Pg: 1070 - 1078

A long-term evaluation of once-daily tiotropium in chronic obstructive pulmonary disease.
Periodical: European Respiratory Journal Index Medicus:
Authors: Casaburi R, Mahler DA, Jones PW, Wanner A, San Pedro G, ZuWallack RL, et al ART
Yr: 2002 Vol: 19 Nbr: Abs: Pg: 217 - 224

Effect of hyperoxia on gas exchange and lactate kinetics following exercise onset in non-hypoxemic COPD patients.
Periodical: Chest Index Medicus:
Authors: Somfay A, Porszasz J, Lee S-M, and Casaburi R ART
Yr: 2002 Vol: 121 Nbr: Abs: Pg: 393 - 400

Adjunctive pharmacologic treatment in chronic obstructive pulmonary disease.
Periodical: European Respiration Rev Index Medicus:
Authors: Casaburi R ART
Yr: 0 Vol: Nbr: Abs: Pg:

A new anticholinergic bronchodilator for chronic obstructive pulmonary disease.
Periodical: European Respiration Rev Index Medicus:
Authors: Casaburi R, van Noord JA, and Witek TJ ART
Yr: 0 Vol: Nbr: Abs: Pg:

Testosterone-induced increase inmuscle size in healthy, young men is associated with muscle fiber hypertrophy.
Periodical: American Journal of Physiology Endocrinology and Metabolism Index Medicus:
Authors: Sinha-Hikim I, Artaza J, Gonzalez-Cadivid N, Singh AB, Casaburi R, Woodhouse L, et al ART
Yr: 2002 Vol: 283 Nbr: Abs: Pg: E154 - E164

Testosterone dose response relationships in health young men.
Periodical: Journal of Investigative Medicine Index Medicus:
Authors: Storer TW, Casaburi R, Singh AB, Magliano L, Bhasin D, Dzekov C, Dzekov J, et al ABS
Yr: 2001 Vol: 49 Nbr: 1 Abs: Pg: 16A

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, and Wanger J ABS
Yr: 2001 Vol: 163 Nbr: 5 Abs: Pg: A503

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, and Casaburi R ABS
Yr: 2001 Vol: 163 Nbr: 5 Abs: Pg: A267

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, and Casaburi R ABS
Yr: 2001 Vol: 163 Nbr: 5 Abs: Pg: A267

A randomized trial of strength training and testosterone supplementation in men with chronic obstructive pulmonary disease.
Periodical: European Respiratory Journal Index Medicus:
Authors: Casaburi R, Consentino G, Bhasin S, Fournier M, Lewis M, Porszasz J, and Storer T ABS
Yr: 2001 Vol: 18 Nbr: Suppl 33 Abs: Pg: 173S

Effect of hyperoxia on gas exchange and lactate kinetics following exercise onset in non-hypoxemic COPD patients.
Periodical: American Journal of Respiratory and Critical Care Medicine Index Medicus:
Authors: Porszasz J, Somfay A, Lee SM, and Casaburi R ABS
Yr: 2002 Vol: 165 Nbr: 8 Abs: Pg: A503

Hormonal and safety profile resulting from physiologic testosterone supplementation in men with COPD.
Periodical: American Journal of Respiratory and Critical Care Medicine Index Medicus:
Authors: Casaburi R, Cosentino L, Porszasz J, Bhasin S, and Storer T ABS
Yr: 2002 Vol: 165 Nbr: 8 Abs: Pg: A506

Spiriva(R) (Tiotropium) reduces lung hyperinflation in COPD.
Periodical: American Journal of Respiratory and Critical Care Medicine Index Medicus:
Authors: Magnussen H, O'Donnel DE, Casaburi R, Kesten S, Gerken F, and Fluge T ABS
Yr: 2002 Vol: 165 Nbr: 8 Abs: Pg: A227

Testosterone replacement and resistance training improve muscle and physical function in men with COPD.
Periodical: Medicine and Science in Sports and Exercise Index Medicus:
Authors: Storer T, Magliano L, Cosentino G, Walsh D, Bhasin S and Casaburi R ABS
Yr: 2002 Vol: 34 Nbr: 5, Suppl Abs: Pg:

Dysfonction musculaire peripherique dans la bronchopneumopathie chronique obstructive.
Periodical: Rev. Mal. Respir. Index Medicus:
Authors: Maltais F, Le Blanc P, Jobin J, Casaburi ART
Yr: 2002 Vol: 19 Nbr: Abs: Pg: 444-453

The range of outcome measures used to evaluate treatment in chronic obstructive pulmonary disease.
Periodical: European Respiration Rev Index Medicus:
Authors: Casaburi R ART
Yr: 2003 Vol: 12 Nbr: 83 Abs: Pg: 58-60

Long-term effects of a maintenance program after supervised or self-monitored training programmes in patients with COPD.
Periodical: Lung Index Medicus:
Authors: Puente-Maestu L, Luisa M, Pilar S, Jose S, Casaburi R, et al. ART
Yr: 2003 Vol: 181 Nbr: Abs: Pg: 67-78

Benefits of supplemental oxygen in exercise training in non-hypoxemic COPD patients.
Periodical: American Journal of Respiratory and Critical Care Medicine Index Medicus:
Authors: Emtner M, Porszasz J, Burns M, Somfay A, Casaburi R ART
Yr: 2003 Vol: 168 Nbr: Abs: Pg: 1034-1042

A linear treadmill ramp protocol using simultaneous changes in walking speed and grade.
Periodical: Medicine and Science in Sports and Exercise Index Medicus:
Authors: Porszasz J, Casaburi R, Somfay A et al ART
Yr: 2003 Vol: 35 Nbr: Abs: Pg: 1596-1603

Limitation to exercise tolerance in COPD: look to the muscles of ambulation.
Periodical: American Journal of Respiratory and Critical Care Medicine Index Medicus:
Authors: Casaburi R ART
Yr: 2003 Vol: 168 Nbr: Abs: Pg: 409-410

Testosterone-induced muscle fiber hypertrophy is associated with an increase in muscle satellite cell number in healthy young men.
Periodical: Journal of Investigative Medicine Index Medicus:
Authors: Sinha-Hikim I, Woodhouse LJ, Singh AB, Casaburi R, Storer TW, Bhasin S ABS
Yr: 2002 Vol: Nbr: Abs: Pg:

Low intensity endurance training improves muscle function, physical performance, and FFM in hemodialysis.
Periodical: Medicine and Science in Sports and Exercise Index Medicus:
Authors: Storer TW, Casaburi R, Gottron C, Walsh D, Kopple JD ABS
Yr: 2003 Vol: 35 Nbr: 5 Abs: s231 Pg:

Endurance training decreases exercise-induced dynamic hyperinflation in patients with COPD.
Periodical: European Respiratory Journal Index Medicus:
Authors: Porszasz J, Emtner M, Whipp BJ, Goto S, Somfay A, Casaburi R ABS
Yr: 2003 Vol: 22 Nbr: 45 Abs: Pg: 205s

A linear incremental work rate protocol for treadmill ergometry by means of continuous grade and velocity increases.
Periodical: European Society for Respiratory Disease Index Medicus:
Authors: Casaburi R, Porszasz J, Woodhouse L, Somfay A, Whipp BJ ABS
Yr: 2003 Vol: 22 Nbr: 45 Abs: Pg: 89s

Endocrinological disturbances in COPD
Periodical: European Respiratory Journal Index Medicus:
Authors: Creutzberg EC, Casaburi R ART
Yr: 2003 Vol: 22 Nbr: Suppl. 46 Abs: Pg: 76s-80s

Anabolic hormone supplementation as an adjunct to pulmonary rehabilitation.
Periodical: American Journal of Medicine and Sports Index Medicus:
Authors: Casaburi R ART
Yr: 2004 Vol: 6 Nbr: Abs: Pg: 28-31

Lung function improvements with once-daily tiotropium in COPD.
Periodical: American Journal of Medicine Index Medicus:
Authors: Casaburi R, Conscenti CS ART
Yr: 0 Vol: Nbr: Abs: Pg:

Effect of helium breathing on dynamic hyperinflation, minute ventilation and exercise tolerance in severe COPD patients.
Periodical: American Journal of Respiratory and Critical Care Medicine Index Medicus:
Authors: Goto S, Porszasz J, Sakurai S, Whipp BJ, Casaburi R ABS
Yr: 2004 Vol: 169 Nbr: 7 Abs: Pg: A467

Tiotropium augments improvements in dyspnea and health-related quality of life following pulmonary rehabilitation in COPD.
Periodical: American Journal of Respiratory and Critical Care Medicine Index Medicus:
Authors: Cooper CB, Kukafka D, Casaburi R, Kesten S ABS
Yr: 2004 Vol: 169 Nbr: 7 Abs: Pg: A518

Improvement in endurance time with the combination of tiotropium and rehabilitative exercise training in COPD patients.
Periodical: American Journal of Respiratory and Critical Care Medicine Index Medicus:
Authors: Casaburi R, Kakafka D, Cooper C, Wang S, Kesten S ABS
Yr: 2004 Vol: 169 Nbr: 7 Abs: Pg: A756

Work rate selection for constant work rate exercise testing for interventional studies in COPD.
Periodical: American Journal of Respiratory and Critical Care Medicine Index Medicus:
Authors: Casaburi R, Chen C, Porszasz, Whipp BJ ABS
Yr: 2004 Vol: 169 Nbr: 7 Abs: Pg: A770

Cellular and molecular adaptations in skeletal muscle to testosterone and/or resistance training in men with COPD.
Periodical: American Journal of Respiratory and Critical Care Medicine Index Medicus:
Authors: Fournier M, Casaburi R, Storer T, Porszasz J, Bhasin S, Da X, Lewis MI ABS
Yr: 2004 Vol: 169 Nbr: 7 Abs: Pg: A904

Use of physiological calibration to validate gas exchange measurements during exercise.
Periodical: Medicine and Science in Sports and Exercise Index Medicus:
Authors: Porszasz J, Woodhouse LJ, Casaburi R, Nguyen A, Tsurugaya H, Whipp BJ ABS
Yr: 2004 Vol: 36 Nbr: 5 Abs: Pg: S27

Effects of heliox breathing on R-R variability at rest and during exercise in COPD.
Periodical: Medicine and Science in Sports and Exercise Index Medicus:
Authors: Sakurai S, Whipp BJ, Goto S, Casaburi R ABS
Yr: 2004 Vol: 36 Nbr: 5 Abs: Pg: S210

Testosterone dose-dependently increases maximal voluntary strength and leg power, but does not affect fatiguability or specific tension.
Periodical: Journal of Clincal Endocrinology and Metabolism Index Medicus:
Authors: Casaburi R, Storer TW, Magliano K, Woodhouse L, Lee ML, Dzekov C, et al. ART
Yr: 2003 Vol: 88 Nbr: Abs: Pg: 1478 - 1485

Effects of testosterone replacement and resistance training in men with chronic obstructive pulmonary disease.
Periodical: American Journal of Critical Care Medicine Index Medicus:
Authors: Casaburi R, Bhasin S, Cosentino L, Porszasz J, Somfay A, Lewis MI, Fournier M, Storer TW ART
Yr: 2004 Vol: 170 Nbr: Abs: Pg: 870 - 878

Older men are as responsive as young men to the anabolic effects of graded testosterone on the skeletal muscle.
Periodical: Journal of Clincal Endocrinology and Metabolism Index Medicus:
Authors: Casaburi R, Bhasin L, Woodhouse L, Singh AB, Phong R, Lee M, et al. ART
Yr: 2005 Vol: 90 Nbr: Abs: Pg: 678 - 688

Dose-dependent effects of testosterone on sexual function, mood and visuospatial cognition in older men.
Periodical: Journal of Clincal Endocrinology and Metabolism Index Medicus:
Authors: asaburi R, Gray PB, Singh AB, Woodhouse LJ, Storer TW, Dzekov J, Dzekov C, et al. ART
Yr: 2005 Vol: 90 Nbr: Abs: Pg: 3838 - 3846