Journal article
Development of apical hypertrophic cardiomyopathy with age in a transgenic mouse model carrying the cardiac actin E99K mutation
Journal of Muscle Research and Cell Motility, Vol.38(5), pp.421-435
12/2017
DOI: 10.1007/s10974-018-9492-1
PMCID: PMC6003854
PMID: 29582353
Abstract
In both humans and mice, the Glu-99-Lys (E99K) mutation in the cardiac actin gene (ACTC) results in little understood apical hypertrophic cardiomyopathy (AHCM). To determine how cross-bridge kinetics change with AHCM development, we applied sinusoidal length perturbations to skinned papillary muscle fibres from 2- and 5-month old E99K transgenic (Tg) and non-transgenic (NTg) mice, and studied tension and its transients. These age groups were chosen because our preliminary studies indicated that AHCM develops with age. Fibres from 5-month old E99K mice showed significant decreases in tension, stiffness, the rate of the medium-speed exponential process and its magnitude compared to non-transgenic control. The nucleotide association constants increased with age, and they were significantly larger in E99K compared to NTg. However, there were no large differences in the rates of the cross-bridge detachment step, the rates of the force generation step, or the phosphate association constant. Our result on force/cross-bridge demonstrates that the decreased active tension of E99K fibres was caused by a decreased amount of force generated per each cross-bridge. The effects were generally less or insignificant at 2 months. A pCa-tension study showed increased Ca2+-sensitivity (pCa50) with age in both the E99K and NTg sample groups, and pCa50 was significantly larger (but only for 0.05–0.06 pCa units) in E99K than in NTg groups. A significant decrease in cooperativity (n
H) was observed only in 5-month old E99K mice. We conclude that the AHCM-causing ACTC E99K mutation is associated with progressive alterations in biomechanical parameters, with changes smaller at 2 months but larger at 5 months, correlating with the development of AHCM.
Details
- Title: Subtitle
- Development of apical hypertrophic cardiomyopathy with age in a transgenic mouse model carrying the cardiac actin E99K mutation
- Creators
- Li Wang - 0000 0004 1936 8294 grid.214572.7 Department of Anatomy and Cell Biology University of Iowa Iowa City IA 52242 USAFan Bai - 0000 0004 1936 8294 grid.214572.7 Department of Anatomy and Cell Biology University of Iowa Iowa City IA 52242 USAQing Zhang - 0000 0001 0198 0694 grid.263761.7 School of Nursing, Medical College Soochow University Suzhou 215006 Jiangsu ChinaWeihua Song - 0000 0001 2113 8111 grid.7445.2 National Heart and Lung Institute Imperial College London London UKAndrew Messer - 0000 0001 2113 8111 grid.7445.2 National Heart and Lung Institute Imperial College London London UKMasataka Kawai - 0000 0004 1936 8294 grid.214572.7 Department of Anatomy and Cell Biology University of Iowa Iowa City IA 52242 USA
- Resource Type
- Journal article
- Publication Details
- Journal of Muscle Research and Cell Motility, Vol.38(5), pp.421-435
- DOI
- 10.1007/s10974-018-9492-1
- PMID
- 29582353
- PMCID
- PMC6003854
- NLM abbreviation
- J Muscle Res Cell Motil
- ISSN
- 0142-4319
- eISSN
- 1573-2657
- Publisher
- Springer International Publishing; Cham
- Grant note
- BK20150353 / Natural Science Foundation of Jiangsu Province of China HL070041 / National Institutes of Health (http://dx.doi.org/10.13039/100000002) 13GRNT16810043 / American Heart Association (http://dx.doi.org/10.13039/100000968)
- Language
- English
- Date published
- 12/2017
- Academic Unit
- Anatomy and Cell Biology; Internal Medicine
- Record Identifier
- 9984025314702771
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