Therapy for muscle dysfunction in COPD: cellular adaptations

Institution:	Cedars-Sinai Medical Center
Investigator(s):	Michael Lewis, M.D.
Award Cycle:	1998 (Cycle 7)	Grant #: 7RT-0114	Award: $502,904
Subject Area:	Pulmonary Disease
Award Type:	Research Project Awards

Abstracts

Initial Award Abstract

Cigarette smoking is the leading cause of chronic obstructive pulmonary disease (COPD). COPD is characterized by the presence of emphysema (i.e., enlargement and destruction of air sacs) and chronic bronchitis (i.e., excessive mucus production due to enlargement of mucus glands in the airways). Despite optimal medical therapy, patients with severe COPD still exhibit crippling symptoms of breathlessness and poor ability to exercise (even at very low levels of activity). While these symptoms have for many years been attributed solely to the abnormalities of the air sacs and the airways within the lung, there is new evidence suggesting that impaired function of major muscle groups of the legs of patients with COPD play a major role in limiting the ability to exercise or even accomplishing simple tasks of daily living (e.g., dressing, bathing, rising from a chair, etc.). The major objective of this proposal is to characterize directly the specific abnormalities within the muscle fibers making up the major leg muscle groups that account for this abnormal function in patients with COPD. Furthermore, we will evaluate the potential for two important treatment measures to reverse the abnormalities noted within the leg muscle fibers as well as the biological pathway by which these treatments exert their positive effects. This will be accomplished by obtaining tiny samples of thigh leg muscle before and after the treatment aimed at reversing the abnormalities in the legs of these patients. This is easily accomplished using a small needle and standard biopsy technique. The treatment consists of administering either a male hormone (testosterone) and/or leg strength training to male patients with COPD over a 10 week period. The study patients will be randomized into one of 4 groups: 1) Testosterone replacement only; 2) Strength training only; 3) Testosterone replacement with strength training; and 4) No active treatment. A strong rationale for this therapeutic approach is supported by several clinical findings: the association of low blood levels of testosterone in male patients with COPD; improved breathing muscle strength in COPD patients given a testosterone-like drug and the high prevalence of weak limb muscles in patients with severe COPD. Comprehensive studies on muscle tissue of these COPD patients will determine: 1) the identity of the specific types of fibers within their leg muscles; 2) the types of major proteins making up these fibers; 3) the relative size of different muscle fiber types; 4) cellular energy production and utilization within muscle fibers; and 5) the distribution of blood vessels within the muscle. In addition, work from our laboratory suggests that increases in muscle fiber size following the administration of testosterone is linked to a special protein system (known as the IGF-I system). We will therefore evaluate levels of IGF I and the various IGF binding proteins within muscle fibers. These comprehensive cellular and molecular studies would be expected to establish a rational scientific basis for new and important therapeutic approaches to impaired exercise tolerance and quality of life in patients with disabling COPD.

Publications

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, Cosentino G, Bhasin S, et al				ART
Yr: 0	Vol:	Nbr:	Abs:	Pg:

TNF-alpha and diaphragm fiber atrophy with malnutrition.
Periodical: American Journal of Respiratory and Critical Care Medicine			Index Medicus:
Authors: Fournier M, Da XZ, Li H, Lewis MI				ABS
Yr: 2002	Vol: 165	Nbr:	Abs:	Pg: A258

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:	Abs:	Pg:

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, Cosentino G, Bhasin S, et al				ART
Yr: 0	Vol:	Nbr:	Abs:	Pg:

TNF-alpha and diaphragm fiber atrophy with malnutrition.
Periodical: American Journal of Respiratory and Critical Care Medicine			Index Medicus:
Authors: Fournier M, Da XZ, Li H, Lewis MI				ABS
Yr: 2002	Vol: 165	Nbr:	Abs:	Pg: A258

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:	Abs:	Pg: