and Specific Aims.) Atrophy of skeletal muscle in humans begins in the third decade of life, but its functional significance is not realized until many decades later (when elderly people have reductions in skeletal muscle mass and strength below that required for independence in daily activities).The mechanisms of the aging- associated atrophy of skeletal muscle have not been established.However, strength training, such as weight lifting, can prevent the loss of muscle mass between the ages of 50-70 years (before senescence) in humans. A component of strength training, eccentric exercise (lengthening contractions), increases insulin-like growth factor-I (IGF-I) immunoreactivity within muscle fibers of young rats. Increases in IGF-I peptide and mRNA have been shown to be associated with muscle hypertrophy in tissue culture and in the work overload model, respectively. Conversely, IGF-I mRNA is decreased in skeletal muscle of young rats when the muscle was not allowed to support the load of body weight (which could be analogous to the decreased mobility or activity by older people). Thus, a potential relationship between weight-bearing exercise, IGF-I expression, and muscle size is suggested.
Four Specific Aims will be tested. First, is the IGF system different between senescent and adult muscle? Does aging reduce the IGF system concurrent with atrophy of skeletal muscle? Measurements include mRNAs for IGFs and insulin- like growth factor binding proteins (IGFBPs), secretion of IGFs and IGFBPs from muscle, and receptor binding densities for IGF and growth hormone on muscle. Second, does the IGF system respond to a given bout of exercise differently between adult and senescent rats? Can eccentric exercise increase the IGF system in senescent muscle?Third, does senescent muscle have an insufficient IGF system to allow major regrowth from prior atrophy? Fourth, can the implantation of neonatal satellite cells, either with or without constitutive expression of IGF-I, into senescent muscle reverse the atrophy of senescent muscle? Does it take IGF-I peptide alone, or eccentric exercise alone, or both reverse atrophy in fast-type skeletal muscle between the ages of 21-24 months in Fischer 344 rats? These Specific Aims may help determine whether causal relationships exist between reductions in muscle activity, changes in IGF expression/modulation, and muscle atrophy in senescent rats. The potential significance of this application is that alterations of the IGF- I system will be tested as a possible mechanism for the atrophy of skeletal muscle with aging.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
3R01AR041995-04S1
Application #
2081182
Study Section
Lung Biology and Pathology Study Section (LBPA)
Project Start
1993-08-01
Project End
1998-07-31
Budget Start
1996-08-01
Budget End
1998-07-31
Support Year
4
Fiscal Year
1996
Total Cost
Indirect Cost
Name
University of Texas Health Science Center Houston
Department
Physiology
Type
Schools of Medicine
DUNS #
City
Houston
State
TX
Country
United States
Zip Code
77225
Tseng, B S; Cavin, S T; Booth, F W et al. (2000) Pulmonary hypoplasia in the myogenin null mouse embryo. Am J Respir Cell Mol Biol 22:304-15
Marsh, D R; Carson, J A; Stewart, L N et al. (1998) Activation of the skeletal alpha-actin promoter during muscle regeneration. J Muscle Res Cell Motil 19:897-907
Gomes Jr, R R; Booth, F W (1998) Expression of acetylcholine receptor mRNAs in atrophying and nonatrophying skeletal muscles of old rats. J Appl Physiol 85:1903-8
Marsh, D R; Hinds, L R; Lester, W S et al. (1998) The force-frequency relationship is altered in regenerating and senescent rat skeletal muscle. Muscle Nerve 21:1265-74
Marsh, D R; Criswell, D S; Hamilton, M T et al. (1997) Association of insulin-like growth factor mRNA expressions with muscle regeneration in young, adult, and old rats. Am J Physiol 273:R353-8
Marsh, D R; Criswell, D S; Carson, J A et al. (1997) Myogenic regulatory factors during regeneration of skeletal muscle in young, adult, and old rats. J Appl Physiol 83:1270-5
Hamilton, M T; Marsh, D R; Criswell, D S et al. (1995) No effect of aging on skeletal muscle insulin-like growth factor mRNAs. Am J Physiol 269:R1183-8
Tseng, B S; Marsh, D R; Hamilton, M T et al. (1995) Strength and aerobic training attenuate muscle wasting and improve resistance to the development of disability with aging. J Gerontol A Biol Sci Med Sci 50 Spec No:113-9
Booth, F W; Weeden, S H; Tseng, B S (1994) Effect of aging on human skeletal muscle and motor function. Med Sci Sports Exerc 26:556-60