A study of tropomyosin's role in cardiac function and disease using thin-filament reconstituted myocardium

Fan Bai; Li Wang; Masataka Kawai

doi:10.1007/s10974-013-9343-z

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A study of tropomyosin's role in cardiac function and disease using thin-filament reconstituted myocardium

Journal article

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A study of tropomyosin's role in cardiac function and disease using thin-filament reconstituted myocardium

Fan Bai, Li Wang and Masataka Kawai

Journal of muscle research and cell motility, Vol.34(3-4), pp.295-310

08/2013

DOI: 10.1007/s10974-013-9343-z

PMCID: PMC3849125

PMID: 23700264

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https://www.ncbi.nlm.nih.gov/pmc/articles/3849125View

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Abstract

Tropomyosin (Tm) is the key regulatory component of the thin-filament and plays a central role in the cardiac muscle's cooperative activation mechanism. Many mutations of cardiac Tm are related to hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), and left ventricular noncompaction (LVNC). Using the thin-filament extraction/reconstitution technique, we are able to incorporate various Tm mutants and protein isoforms into a muscle fiber environment to study their roles in Ca(2+) regulation, cross-bridge kinetics, and force generation. The thin-filament reconstitution technique poses several advantages compared to other in vitro and in vivo methods: (1) Tm mutants and isoforms are placed into the real muscle fiber environment to exhibit their effect on a level much higher than simple protein complexes; (2) only the primary and immediate effects of Tm mutants are studied in the thin-filament reconstituted myocardium; (3) lethal mutants of Tm can be studied without causing a problem; and (4) inexpensive. In transgenic models, various secondary effects (myocyte disarray, ECM fibrosis, altered protein phosphorylation levels, etc.) also affect the performance of the myocardium, making it very difficult to isolate the primary effect of the mutation. Our studies on Tm have demonstrated that: (1) Tm positively enhances the hydrophobic interaction between actin and myosin in the "closed state", which in turn enhances the isometric tension; (2) Tm's seven periodical repeats carry distinct functions, with the 3rd period being essential for the tension enhancement; (3) Tm mutants lead to HCM by impairing the relaxation on one hand, and lead to DCM by over inhibition of the AM interaction on the other hand. Ca(2+) sensitivity is affected by inorganic phosphate, ionic strength, and phosphorylation of constituent proteins; hence it may not be the primary cause of the pathogenesis. Here, we review our current knowledge regarding Tm's effect on the actomyosin interaction and the early molecular pathogenesis of Tm mutation related to HCM, DCM, and LVNC.

Animals

Cardiomyopathy, Dilated - metabolism

Cardiomyopathy, Dilated - physiopathology

Cardiomyopathy, Hypertrophic - metabolism

Cardiomyopathy, Hypertrophic - physiopathology

Heart - physiology

Heart Diseases - genetics

Heart Diseases - metabolism

Humans

Myocardium - metabolism

Myocardium - pathology

Tropomyosin - chemistry

Tropomyosin - genetics

Tropomyosin - metabolism

Details

Title: Subtitle: A study of tropomyosin's role in cardiac function and disease using thin-filament reconstituted myocardium
Creators: Fan Bai - University of Iowa
Li Wang - University of Iowa
Masataka Kawai - University of Iowa
Resource Type: Journal article
Publication Details: Journal of muscle research and cell motility, Vol.34(3-4), pp.295-310
DOI: 10.1007/s10974-013-9343-z
PMID: 23700264
PMCID: PMC3849125
NLM abbreviation: J Muscle Res Cell Motil
ISSN: 0142-4319
eISSN: 1573-2657
Grant note: R01 HL070041 / NHLBI NIH HHS HL70041 / NHLBI NIH HHS
Language: English
Date published: 08/2013
Academic Unit: Anatomy and Cell Biology; Internal Medicine
Record Identifier: 9984284345602771

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