In skeletal muscle a large number of contractile protein isoforms are expressed. Our goal is to understand how the expression of these different isoforms is controlled and how they affect fiber physiology. During the first six years of this award, we established the biochemical and physiological foundation for these studies. Applying high resolution SDS-PAGE and HPLC, monoclonal antibodies and aminoacid sequence analyses in combination with physiological studies we: 1) identified three major programs of troponin-tropomyosin expression in fast skeletal muscle fibers 2) found that the coexpression of these programs in different ratios in muscle fibers results in a molecular continuum of fast fibers and 3) demonstrated that this molecular continuum determines the continuum of physiological and ultrastructural properties of fast fibers. These observations led us to develop new ways of thinking about contractile protein, and this in turn has resulted in a shift in our research emphasis to the cellular mechanisms that regulate coexpression of different thin filament programs we have defined. In these studies, we will establish the basis for a molecular understanding of the ways the different TnT-Tm programs control the physiological response to calcium; and using a variety of approaches, including microinjection pulse labelling oligo probes and eukaryotic expression vectors, will identify the mechanisms that control tropomyosin transcription and translation and coordinate its expression with that ofthe different alternatively spliced troponin T isoforms.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR037344-09
Application #
3158070
Study Section
Molecular Cytology Study Section (CTY)
Project Start
1986-01-01
Project End
1993-12-31
Budget Start
1991-01-01
Budget End
1991-12-31
Support Year
9
Fiscal Year
1991
Total Cost
Indirect Cost
Name
Duke University
Department
Type
Schools of Medicine
DUNS #
071723621
City
Durham
State
NC
Country
United States
Zip Code
27705