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Mechanisms underlying diaphragm adaptations in emphysema

Institution: Cedars-Sinai Medical Center
Investigator(s): Mario Fournier, Ph.D.
Award Cycle: 1998 (Cycle 7) Grant #: 7RT-0161 Award: $642,624
Subject Area: Pulmonary Disease
Award Type: Research Project Awards
Abstracts

Initial Award Abstract
Cigarette smoking is the most common cause of emphysema (i.e., enlargement and destruction of air sacs in the lung). Despite optimal medical therapy, patients with severe emphysema still exhibit crippling symptoms of breathlessness and poor exercise ability. Moreover, important complications of this condition (e.g., malnutrition) or adverse side effects of drugs (e.g., corticosteroids) may add to the already high rate of morbidity and/or mortality of emphysema. Recently, anabolic steroids have been used in undernourished patients with emphysema in an attempt to improve breathing and limb muscle function. Our laboratory has considerable experience in evaluating the adaptations of the diaphragm (the most important breathing muscle) and other breathing muscles in an animal (hamster) model of emphysema using functional, cellular and biochemical approaches, as well as assessing the confounding impacts of malnutrition and corticosteroids or the influence of growth promoting agents on diaphragm function. This approach allows one to directly address, at the tissue or cellular level, complications of the disease process or side effects of commonly utilized therapies that would be neither ethical nor practical to evaluate in humans. Recent provocative data in the literature and from our own laboratory suggest that an important protein growth factor, called insulin-like growth factor-I (IGF-I), plays a major role in determining the size and function of muscle fibers in general, including the responses of the diaphragm to its increased workload imposed by emphysema. The overall objective of this proposal is to examine the potential role of the muscle IGF-I system in determining changes in diaphragm muscle fibers. Furthermore, we propose to examine the potential mechanisms whereby this local IGF-I system determines the adverse effects of malnutrition and corticosteroids, in contrast to the positive effects of anabolic steroids, on these specific muscle fibers. We hypothesize that the enlargement of diaphragm fibers in emphysema or following anabolic steroid treatment may in part be due to an increase in IGF-I production and/or availability within specific diaphragm fibers. By contrast conditions associated with shrinkage of specific fibers (e.g., malnutrition or use of corticosteroids) may be associated with decreased levels of IGF-I. Detailed studies will be performed to ascertain the following: (1) levels of IGF-I and related proteins within muscle; (2) the activity of specialized cells responsible for muscle fiber growth (satellite cells); and (3) the types, size and proteins that make up individual muscle fibers in the diaphragm. These studies will provide much needed insight into the mechanisms responsible for diaphragm muscle fiber changes with emphysema, as well as those associated with the adverse effects of common disease complications and drug use, and into the therapeutic potential for new muscle growth-promoting agents. Development of alternative therapies is especially important since only a minority of patients with severe emphysema would likely be eligible for newer surgical therapies such as lung transplantation or lung volume reduction surgery (which remains experimental at this time).
Publications

IGF-1 administration prevents corticosteroid-induced diaphragm atrophy in emphysematous hamsters
Periodical: American Journal of Respiratory and Critical Care Medicine Index Medicus:
Authors: Lewis MI, Bulut Y, Biring MS, Da X, Fournier M ART
Yr: 1999 Vol: 159 Nbr: Abs: Pg: A580

Influences of corticosteroids on diaphragm muscle IGF-1 and ubiquitin-conjugating enzyme E2-14k
Periodical: American Journal of Respiratory and Critical Care Medicine Index Medicus:
Authors: Fournier M, Huang Z-S, Lewis MI ART
Yr: 2000 Vol: 161 Nbr: Abs: Pg: A119

The influence of varying degrees of malnutrition on insulin-like growth factor-1 in rat diaphragm
Periodical: American Journal of Respiratory and Critical Care Medicine Index Medicus:
Authors: Lewis MI, Huang Z-S, Bykhovskaya I, et al ART
Yr: 2000 Vol: 161 Nbr: Abs: Pg: A18

Administration of insulin-like growth factor-1 (IGF-1) and corticosteroids in emphysematous hamsters: influences on diaphragm IGF-1
Periodical: American Journal of Respiratory and Critical Care Medicine Index Medicus:
Authors: Fournier M, Huang Z-S, Cercek B, Li H, Bykhovskaya I, Lewis MI ART
Yr: 2000 Vol: 161 Nbr: Abs: Pg: A18

Early cellular responses in diaphragm fibers of emphysematous hamsters following lung volume reduction surgery (LVRS)
Periodical: American Journal of Respiratory and Critical Care Medicine Index Medicus:
Authors: Lewis MI, Da X, Mohsenifar Z, Fournier M ABS
Yr: 2001 Vol: 163 Nbr: Abs: A286 Pg:

Diaphragm IGF-1 responses to lung volume reduction surgery (LVRS) in emplysematous hamsters
Periodical: American Journal of Respiratory and Critical Care Medicine Index Medicus:
Authors: Fournier M, Li H, Da X, Mohsenifar Z, Lewis MI ABS
Yr: 2001 Vol: 163 Nbr: Abs: A147 Pg:

Diaphragm IGF-1 responses to nandrolone in malnourished emphysematous hamsters
Periodical: American Journal of Respiratory and Critical Care Medicine Index Medicus:
Authors: Fournier M, Li H, Da X, Biring MS, Lewis MI ABS
Yr: 2001 Vol: 163 Nbr: Abs: A147 Pg:

Role of IGF-1 and IGF binding proteins within diaphragm muscle in modulating the effects of nandrolone.
Periodical: American Journal of Physiology Endocrinology and Metabolism Index Medicus:
Authors: Lewis MI, Horvitz GD, Clemmons DR, Fournier M ART
Yr: 2002 Vol: 282 Nbr: Abs: Pg: E483-E490

influence of varying degrees of malnutrition on IGF-i expression in the rat diaphragm.
Periodical: American Journal of Physiology Index Medicus:
Authors: Lewis MI, Li H, Huang ZS, Biring MS, Cercek B, Fournier M ART
Yr: 2003 Vol: 95 Nbr: Abs: Pg: 555-562

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

Influence of short-term malnutrition on muscle IGF-1 signaling pathways.
Periodical: American Journal of Respiratory and Critical Care Medicine Index Medicus:
Authors: Lewis MI, Kamangar N, Xu NX, Da X, Fournier M ABS
Yr: 2003 Vol: 167 Nbr: Abs: Pg: A963

Skeletal muscle gene expression profile in response to short-term malnutrition.
Periodical: American Journal of Respiratory and Critical Care Medicine Index Medicus:
Authors: Fournier M, Wang C, Kamangar N, Li H, Chen Y-DI, Lewis MI ABS
Yr: 2003 Vol: 167 Nbr: Abs: Pg: A963