In humans and animals, exercise and other forms of increased contractile activity are known to inhibit the muscle wasting associated with diseases and experimental conditions resulting from glucocorticoid excess. Recent evidence also indicates that preserving muscle glutamine concentration has the potential to serve as another therapeutic deterrent to muscle atrophy. By examining hormone-responsive, up- regulated (glutamine synthetase, GS) and down-regulated (myosin heavy chains) genes as models for understanding protein regulation, the long- term objectives are to elucidate the molecular events by which exercise and glutamine therapy prevents atrophy from this state. The first overall goal (aims one and two) is: to determine whether maintaining muscle glutamine concentration by glutamine supplementation prevents muscle wasting from glucocorticoids; to evaluate whether glutamine regulates glutamine synthetase expression at a posttranslational level; To determine whether preserving muscle glutamine concentration interferes with the glucocorticoid-mediated depression of myosin heavy chain synthesis; and to examine whether the combination of exercise and glutamine therapy can produce additive effect in atrophy prevention. A second research goal (aims three and four) is directed at examining whether alpha-ketoglutarate supplementation prevents atrophy through maintenance of muscle glutamine levels; whether alpha-ketoglutarate can antagonize hormone-mediated changes in glutamine synthetase expression and in myosin heavy chain synthesis; and whether the combination of glutamine and alpha-ketoglutarate supplementation are essential for optimally preserving muscle glutamine and in protecting against-atrophy. Results from the present grant period have shown that increased contractile activity diminishes basal and glucorticoid-induced GS enzyme activity and mRNA content. Consequently, using transgenic animals, a third goal (aim five) will determine whether the endurance training effects on GS are: (a) indicative of a generalized glucocorticoid response in muscle; (b) director at promoter elements on the GS gene; and (c) directed at an activating transcription factor/cyclic AMP- response element enhancer region of the gene. This project will establish the extent of the individual and combined contributions of glutamine, alpha-ketoglutarate, and exercise in producing optimal therapeutic conditions against atrophy. These results will further establish the importance of GS in the regulation of muscle mass and the mechanism of its gene regulation by exercise. New basic knowledge can be obtained into the reported anabolic effects of glutamine on protein synthesis and the relationship of these alterations with preservation of muscle mass. An understanding of the mechanisms associated with this type of atrophy and atrophy prevention can provide the basis for therapy as well as in identifying the mechanisms underlying other types of muscle wasting conditions and diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
2R01AR039496-04
Application #
3159559
Study Section
Cardiovascular and Renal Study Section (CVB)
Project Start
1989-04-01
Project End
1996-05-31
Budget Start
1992-06-01
Budget End
1993-05-31
Support Year
4
Fiscal Year
1992
Total Cost
Indirect Cost
Name
University of Illinois at Chicago
Department
Type
Schools of Allied Health Profes
DUNS #
121911077
City
Chicago
State
IL
Country
United States
Zip Code
60612
Hickson, R C; Oehler, D T; Byerly, R J et al. (1997) Protective effect of glutamine from glucocorticoid-induced muscle atrophy occurs without alterations in circulating insulin-like growth factor (IGF)-I and IGF-binding protein levels. Proc Soc Exp Biol Med 216:65-71
Hickson, R C; Wegrzyn, L E; Osborne, D F et al. (1996) Glutamine interferes with glucocorticoid-induced expression of glutamine synthetase in skeletal muscle. Am J Physiol 270:E912-7
Hickson, R C; Wegrzyn, L E; Osborne, D F et al. (1996) Alanyl-glutamine prevents muscle atrophy and glutamine synthetase induction by glucocorticoids. Am J Physiol 271:R1165-72
Hickson, R C; Czerwinski, S M; Wegrzyn, L E (1995) Glutamine prevents downregulation of myosin heavy chain synthesis and muscle atrophy from glucocorticoids. Am J Physiol 268:E730-4
Marone, J R; Falduto, M T; Essig, D A et al. (1994) Effects of glucocorticoids and endurance training on cytochrome oxidase expression in skeletal muscle. J Appl Physiol 77:1685-90
Hickson, R C; Marone, J R (1993) Exercise and inhibition of glucocorticoid-induced muscle atrophy. Exerc Sport Sci Rev 21:135-67
Falduto, M T; Young, A P; Smyrniotis, G et al. (1992) Reduction of glutamine synthetase mRNA in hypertrophied skeletal muscle. Am J Physiol 262:R1131-6
Falduto, M T; Young, A P; Hickson, R C (1992) Exercise inhibits glucocorticoid-induced glutamine synthetase expression in red skeletal muscles. Am J Physiol 262:C214-20
Falduto, M T; Young, A P; Hickson, R C (1992) Exercise interrupts ongoing glucocorticoid-induced muscle atrophy and glutamine synthetase induction. Am J Physiol 263:E1157-63
Falduto, M T; Czerwinski, S M; Hickson, R C (1990) Glucocorticoid-induced muscle atrophy prevention by exercise in fast-twitch fibers. J Appl Physiol 69:1058-62

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