and Specific Aims.) In emphysema (EMP), significant increases in lung volume, particularly when accompanied by dynamic hyperinflation, impose a chronic persistent load on the diaphragm (DIA) (122) which results in a number of adaptations in the DIA muscle. Corticosteroids are commonly used in patients with chronic obstructive pulmonary disease (COPD) either during exacerbations of the condition or as maintenance therapy in a subset of these patients. While it is well known that corticosteroids in and of themselves can affect muscle structure and function, there is little objective data on the interactive influences of corticosteroids and EMP on DIA performance. Growth factors such as anabolic steroids, growth hormone (GH) or insulin-like growth factor-I (IGF-I) may exert a positive influence on muscle function, but have only been used experimentally in patients with COPD. The overall objective is therefore to examine the interaction between EMP and currently used (corticosteroids) and possible (growth factors) therapeutic agents on DIA structure and function.
The Specific Aims are: 1) to examine independently the impact of EMP, corticosteroids, anabolic steroids and IGF-I on: a) mechanical properties of the DIA - a) DIA specific force (i,e., force/unit/cross- sectional area), b) maximum velocity of shortening; and c) fatigue resistance; b) Fiber type proportions and fiber cross-sectional areas; c) Myosin heavy chain composition; and d) Oxidative enzyme capacity; and 2) to examine the interactions between EMP and either corticosteroids, anabolic steroids or IGF- I on the DIA structure and function, as outlined above.It is hypothesized that EMP, corticosteroids, anabolic steroids and IGF-I influence myosin heavy chain isoform expression and/or oxidative enzyme activity and, therefore, alter the contractile and fatigue properties of the DIA muscle. It is further hypothesized that the effects of corticosteroids, anabolic steroids, and IGF-I are interactive with those of EMP.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
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Lung Biology and Pathology Study Section (LBPA)
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Cedars-Sinai Medical Center
Los Angeles
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Fournier, Mario; Huang, Zhi-Shen; Li, Hongyan et al. (2003) Insulin-like growth factor I prevents corticosteroid-induced diaphragm muscle atrophy in emphysematous hamsters. Am J Physiol Regul Integr Comp Physiol 285:R34-43
Lewis, Michael I; Li, Hongyan; Huang, Zhi-Shen et al. (2003) Influence of varying degrees of malnutrition on IGF-I expression in the rat diaphragm. J Appl Physiol 95:555-62
Lewis, Michael I; Horvitz, Gail D; Clemmons, David R et al. (2002) Role of IGF-I and IGF-binding proteins within diaphragm muscle in modulating the effects of nandrolone. Am J Physiol Endocrinol Metab 282:E483-90
Fournier, M; Lewis, M I (2000) Functional, cellular, and biochemical adaptations to elastase-induced emphysema in hamster medial scalene. J Appl Physiol 88:1327-37
Fournier, M; Lewis, M I (2000) Influences of IGF-I gene disruption on the cellular profile of the diaphragm. Am J Physiol Endocrinol Metab 278:E707-15
Lewis, M I; Fournier, M; Yeh, A Y et al. (1999) Alterations in diaphragm contractility after nandrolone administration: an analysis of potential mechanisms. J Appl Physiol 86:985-92
Biring, M S; Fournier, M; Ross, D J et al. (1998) Cellular adaptations of skeletal muscles to cyclosporine. J Appl Physiol 84:1967-75
Lewis, M I; Feinberg, A T; Fournier, M (1998) IGF-I and/or growth hormone preserve diaphragm fiber size with moderate malnutrition. J Appl Physiol 85:189-97
Sullivan, K J; Fournier, M; Lewis, M I (1998) Respiratory work in elastase treated hamsters. Respir Physiol 114:133-42
Lewis, M I; LoRusso, T J; Fournier, M (1997) Effect of insulin-like growth factor I and/or growth hormone on diaphragm of malnourished adolescent rats. J Appl Physiol 82:1064-70

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