Abstract

The overall objective of this project is to evaluate the intracellular mechanisms which alter the skeletal muscle function during the known progression of muscle dystrophies in genetically inbred cardiomyopathic Syrian hamsters and in humans with Duchhene muscular dystrophy. This strain of hamsters provides a reliably reproducible model of muscular dystrophy and congestive heart failure, and allows systematic studies of the myopathic processes. Human biopsy studies would allow direct application of this knowledge to the disease. These studies will be made with simplified skinned fiber preparations of muscles to rule out the complicating effects of heterogeneity and extracellular connective tissue. Such preparations will be obtained from psoas (fast muscle) and soleus (slow muscle) fibers in hamsters and from biopsies of quadriceps and gastrocnemius muscles and Duchhene patients. One specific objective is to measure the contraction properties of preparations of randomly selected fibers from each of the muscles, to determine a range of contraction properties within a given muscle and effect of the disease on this distribution. The physiological studies will be correlated with a morphological and histochemical changes in the sampled muscle as well as in the fiber studied. Therefore, the study will help with better characterizing the muscle disease and provide critical tests of the various hypotheses for pathogenesis of myopathy. The Ca and Sr sensitivity of force development and of intrinsic shortening speed will be measured to evaluate the changes in the regulation mechanism in the disease at several selected stages of development. Similarly, the sensitivity of these parameters to ionic strength will be determined to evaluate changes in properties of the specific rate constants of the cross-bridge turnover mechanism. Such studies will be made of the contraction transients as well and will be carried out for 30 days, 75 days, 150 days and 300 days hamsters. Another long term objective of the project is to evaluate the effects of therapeutic drugs (verapamil, isoproteronal and prazosin) on the various contraction derived from these studies of this project will help in the understanding as well as the cure of muscular dystrophy and also possibly of the myocardial failure in congestive disease.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR033736-03
Application #
3156645
Study Section
Cardiovascular Study Section (CVA)
Project Start
1984-12-01
Project End
1987-11-30
Budget Start
1986-12-01
Budget End
1987-11-30
Support Year
3
Fiscal Year
1987
Total Cost
Indirect Cost

  Institution

Name
Albert Einstein College of Medicine
Department
Type
Schools of Medicine
DUNS #
009095365
City
Bronx
State
NY
Country
United States
Zip Code
10461

  Publications

Akella, A B; Su, H; Sonnenblick, E H et al. (1997) The cardiac troponin C isoform and the length dependence of Ca2+ sensitivity of tension in myocardium. J Mol Cell Cardiol 29:381-9
Ding, X L; Akella, A B; Sonnenblick, E H et al. (1996) Molecular basis of depression of Ca2+ sensitivity of tension by acid pH in cardiac muscles of the mouse and the rat. J Card Fail 2:319-26
Akella, A B; Sonnenblick, E H; Gulati, J (1996) Alterations in myocardial contractile proteins in diabetes mellitus. Coron Artery Dis 7:124-32
Ding, X L; Akella, A B; Gulati, J (1995) Contributions of troponin I and troponin C to the acidic pH-induced depression of contractile Ca2+ sensitivity in cardiotrabeculae. Biochemistry 34:2309-16
Gulati, J; Akella, A B; Su, H et al. (1995) Functional role of arginine-11 in the N-terminal helix of skeletal troponin C: combined mutagenesis and molecular dynamics investigation. Biochemistry 34:7348-55
Rao, V G; Akella, A B; Su, H et al. (1995) Molecular mobility of the Ca(2+)-deficient EF-hand of cardiac troponin C as revealed by fluorescence polarization of genetically inserted tryptophan. Biochemistry 34:562-8
Akella, A B; Ding, X L; Cheng, R et al. (1995) Diminished Ca2+ sensitivity of skinned cardiac muscle contractility coincident with troponin T-band shifts in the diabetic rat. Circ Res 76:600-6
Ding, X L; Akella, A B; Su, H et al. (1994) The role of glycine (residue 89) in the central helix of EF-hand protein troponin-C exposed following amino-terminal alpha-helix deletion. Protein Sci 3:2089-96
Keleti, D; Rao, V G; Su, H et al. (1994) Disparate contributions of Tyr10 and Tyr109 to fluorescence intensity of rabbit skeletal muscle troponin C identified using a genetically engineered mutant. FEBS Lett 354:135-9
Gulati, J; Rao, V G (1994) The cardiac Ca(2+)-deficient EF-hand governs the phenotype of the cardiac-skeletal TnC-chimera in solution by Sr(2+)-induced tryptophan fluorescence emission. Biochemistry 33:9052-6

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