A long-term aim is to delineate the mechanisms by which chronic changes in contractile activity alter the phenotypic expression of skeletal muscle. In the regrowth of of atrophied skeletal muscle after ending limb immobilization, all proteins increase in response to normal muscle usage. Further increases in all proteins in normal adult skeletal muscles are only possible if it undergoes maximal loading exercise, such as weight-lifting. In contrast, repetitive, low-intensity exercise like running results in no enlargement of normal muscle, but causes an preferential expression of mitochondrial proteins, such as cytochrome c. A strategy of the present application is to compare the responses of mrna levels, protein synthetic machinery and potential molecular signals controlling the upregulation of specific protein quantities in different types of exercises known to cause various phenotypic expressions. The following methods will be employed in the comparison among exercises. In situ hybridization will permit the localization of transcripts to nuclei by using intron probes, so a determination can be made as the time when changes in the levels of specific nuclear transcripts occur after the exercise and for which transcripts. The four cytochrome c mRNAs will be isolated from a cDNA library, cloned, sequenced and translated so as to provide information on the functional significance of shifts in their relative profiles which occur during regrowth from atrophy and during a program of repeated daily bouts of running. A rat genomic library will be screened for fragments containing 5' upstream and coding sequences for somatic cytochrome c, a skeletal actin, fast myosin-heavy-chain and rRNA for the purposes of obtaining intron probes for in situ hybridization. Also, the 5' stream sequences will be used for a further proposal to study regulatory sequences for gene expression. In accordance with this long-range plan, studies are initiated in the present application to identify potential candidates for signals which may interact,directly r indirectly through a cascade, with the 5' untranscribed regulatory region of the genome. The potential roles of the oncogenes, ATP, creatine phosphate, H+, and Ca++as the linkers from increased muscle usage to differential gene expression will be considered.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37AR019393-17
Application #
3481475
Study Section
Respiratory and Applied Physiology Study Section (RAP)
Project Start
1979-08-01
Project End
1996-04-30
Budget Start
1993-05-01
Budget End
1994-04-30
Support Year
17
Fiscal Year
1993
Total Cost
Indirect Cost
Name
University of Texas Health Science Center Houston
Department
Type
Schools of Medicine
DUNS #
City
Houston
State
TX
Country
United States
Zip Code
77225
Spangenburg, Espen E; Booth, Frank W (2006) Leukemia inhibitory factor restores the hypertrophic response to increased loading in the LIF(-/-) mouse. Cytokine 34:125-30
Machida, S; Booth, F W (2005) Changes in signalling molecule levels in 10-day hindlimb immobilized rat muscles. Acta Physiol Scand 183:171-9
Lees, Simon J; Booth, Frank W (2005) Physical inactivity is a disease. World Rev Nutr Diet 95:73-9
Booth, Frank W; Shanely, R Andrew (2004) The biochemical basis of the health effects of exercise: an integrative view. Proc Nutr Soc 63:199-203
Lees, Simon J; Booth, Frank W (2004) Sedentary death syndrome. Can J Appl Physiol 29:447-60; discussion 444-6
Rennie, Michael J; Wackerhage, Henning; Spangenburg, Espen E et al. (2004) Control of the size of the human muscle mass. Annu Rev Physiol 66:799-828
Machida, Shuichi; Booth, Frank W (2004) Regrowth of skeletal muscle atrophied from inactivity. Med Sci Sports Exerc 36:52-9
Spangenburg, Espen E; Bowles, Douglas K; Booth, Frank W (2004) Insulin-like growth factor-induced transcriptional activity of the skeletal alpha-actin gene is regulated by signaling mechanisms linked to voltage-gated calcium channels during myoblast differentiation. Endocrinology 145:2054-63
Chakravarthy, Manu V; Booth, Frank W (2004) Eating, exercise, and ""thrifty"" genotypes: connecting the dots toward an evolutionary understanding of modern chronic diseases. J Appl Physiol 96:3-10
Iyer, Dinakar; Belaguli, Narasimhaswamy; Fluck, Martin et al. (2003) Novel phosphorylation target in the serum response factor MADS box regulates alpha-actin transcription. Biochemistry 42:7477-86

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