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Investigating the Pathogenesis of MYH7 Mutation Gly823Glu in Familial Hypertrophic Cardiomyopathy using a Mouse Model
Published on: August 8, 2022
Development of apical hypertrophic cardiomyopathy with age in a transgenic mouse model carrying the cardiac actin
Li Wang1,2, Fan Bai2, Qing Zhang1
1School of Nursing, Medical College, Soochow University, Suzhou, 215006, Jiangsu, China.
Insights
The Glu-99-Lys (E99K) mutation in cardiac actin causes apical hypertrophic cardiomyopathy (AHCM) by altering cross-bridge kinetics. This mutation progressively reduces muscle tension and force per cross-bridge, particularly in older mice.
Area of Science:
- Cardiovascular Physiology
- Molecular Cardiology
- Biophysics
Background:
- Apical hypertrophic cardiomyopathy (AHCM) is a cardiac disease linked to mutations in the cardiac actin gene (ACTC).
- The specific Glu-99-Lys (E99K) mutation's impact on cardiac muscle biomechanics and cross-bridge kinetics remains poorly understood.
- AHCM development is known to progress with age, suggesting age-dependent changes in affected muscle fibers.
Purpose of the Study:
- To investigate how cross-bridge kinetics are altered during the development of AHCM caused by the ACTC E99K mutation.
- To compare biomechanical properties of cardiac muscle fibers from E99K transgenic (Tg) and non-transgenic (NTg) mice at different ages (2 and 5 months).
- To elucidate the relationship between the E99K mutation, age, and the progression of AHCM.
Main Methods:
- Skinned papillary muscle fibers from 2- and 5-month-old E99K Tg and NTg mice were subjected to sinusoidal length perturbations.
- Measurements included muscle tension, stiffness, and transient responses to perturbations.
- pCa-tension studies were performed to assess calcium sensitivity and cooperativity.
Main Results:
- Five-month-old E99K Tg mice exhibited significantly decreased tension, stiffness, and altered kinetics compared to NTg controls.
- The E99K mutation led to increased nucleotide association constants and a reduced force per cross-bridge, explaining decreased active tension.
- Calcium sensitivity (pCa50) increased with age in both groups, and cooperativity (nH) decreased significantly only in 5-month-old E99K mice.
Conclusions:
- The ACTC E99K mutation causes progressive alterations in cardiac muscle biomechanical parameters, with effects becoming more pronounced with age.
- The reduced force per cross-bridge is a key factor contributing to the decreased active tension observed in E99K mice.
- These age-dependent biomechanical changes correlate with the development and progression of AHCM.
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 (nH) 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.
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