The longterm goal of this project is to define the post- translational steps in the assembly and remodeling of myofibrils of cross-striated muscle. This organelle exhibits characteristic isoform replacements during the course of development and its proteins undergo constant turnover throughout life. Muscle can increase in diameter in response to exercise (work-induced hypertrophy) or atrophy with disuse or in response to protein malnutrition. Myofibrils constitutes the major amino acid store of the body and these can be mobilized for the maintenance of other essential organs, eg. brain, liver, heart, kidneys, etc., upon starvation. We propose to test the hypothesis that polymerized proteins of the sarcomere are in dynamic equilibrium with monomers in the cytoplasm: compositional changes of the myofibrils result from insertion of new proteins into preexisting fibrils rather than the en bloc destruction and reassembly of whole sarcomeres or myofilaments. Seven sets of experiments are planned. 1. In vitro analysis of myofibrillar protein exchange. 2. In vivo analysis of myofibrillar protein pools. 3. Identification and analysis of myosin-binding proteins which regulate thick filament assembly and subunit exchange. 4. Cloning and primary structure determination of muscle C-protein and 86 kD protein. 5. Molecular genetic dissection of the protein domains in myosin required for polymerization and sarcomerogenesis. 6. Analysis of actin isoforms in myofibrillogenesis. 7. Genetic analysis of sarcomere assembly by DNA-mediated gene transfer experiments. These experiments will form the basis of future studies in man directed at the pathogenesis of muscle wasting in myopathies, cachexia associated with neoplasia and aging, and in severe burns.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR032147-12
Application #
3156207
Study Section
Molecular Cytology Study Section (CTY)
Project Start
1982-07-01
Project End
1994-03-31
Budget Start
1993-02-01
Budget End
1994-03-31
Support Year
12
Fiscal Year
1993
Total Cost
Indirect Cost
Name
Weill Medical College of Cornell University
Department
Type
Schools of Medicine
DUNS #
201373169
City
New York
State
NY
Country
United States
Zip Code
10065
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