Journal article
Enhanced Active Cross-Bridges during Diastole: Molecular Pathogenesis of Tropomyosin's HCM Mutations
Biophysical journal, Vol.100(4), pp.1014-1023
02/16/2011
DOI: 10.1016/j.bpj.2011.01.001
PMCID: PMC3037557
PMID: 21320446
Abstract
Three HCM-causing tropomyosin (Tm) mutants (V95A, D175N, and E180G) were examined using the thin-filament extraction and reconstitution technique. The effects of Ca
2+
, ATP, phosphate, and ADP concentrations on cross-bridge kinetics in myocardium reconstituted with each of these mutants were studied at 25°C, and compared to wild-type (WT) Tm at physiological ionic strength (200 mM). All three mutants showed significantly higher (2–3.5 fold) low Ca
2+
tension (
T
LC
) and stiffness than WT at pCa 8.0. High Ca
2+
tension (
T
HC
) was significantly higher for E180G than that for WT, whereas
T
HC
of V95A and D175N was similar to WT; high Ca
2+
stiffness (
Y
HC
) had the same trend. The Ca
2+
sensitivity of isometric force was significantly greater for V95A and E180G than for WT, whereas that of D175N remained the same as for WT; for all mutants, cooperativity was lower than for WT. Nine kinetic constants and the cross-bridge distribution were deduced using sinusoidal analysis. The number of force-generating cross bridges was similar among the D175N, E180G, and WT Tm forms, but it was significantly larger in the case of V95A than WT. We conclude that the increased number of actively cycling cross bridges at pCa 8 is the major cause of Tm mutation-related HCM pathogenesis, which may result in diastolic dysfunction. Decreased contractility (
T
act
) in V95A and D175N may further contribute to the severity of myocyte hypertrophy and related prognosis of the disease.
Details
- Title: Subtitle
- Enhanced Active Cross-Bridges during Diastole: Molecular Pathogenesis of Tropomyosin's HCM Mutations
- Creators
- Fan Bai - Department of Anatomy and Cell Biology, University of Iowa, Iowa City, IowaAdam Weis - Department of Anatomy and Cell Biology, University of Iowa, Iowa City, IowaAya K Takeda - Department of Biological Science, Florida State University, Tallahassee, FloridaP. Bryant Chase - Department of Biological Science, Florida State University, Tallahassee, FloridaMasataka Kawai - Department of Anatomy and Cell Biology, University of Iowa, Iowa City, Iowa
- Resource Type
- Journal article
- Publication Details
- Biophysical journal, Vol.100(4), pp.1014-1023
- Publisher
- The Biophysical Society
- DOI
- 10.1016/j.bpj.2011.01.001
- PMID
- 21320446
- PMCID
- PMC3037557
- ISSN
- 0006-3495
- eISSN
- 1542-0086
- Language
- English
- Date published
- 02/16/2011
- Academic Unit
- Anatomy and Cell Biology; Internal Medicine
- Record Identifier
- 9984025689802771
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