Hypercontractile mutant of ventricular myosin essential light chain leads to disruption of sarcomeric structure and function and results in restrictive cardiomyopathy in mice

Chen Ching Yuan, Katarzyna Kazmierczak, Jingsheng Liang, Rosemeire Kanashiro-Takeuchi, Thomas C. Irving, Aldrin V Gomes, Yihua Wang, Thomas P. Burghardt, Danuta Szczesna-Cordary

Research output: Contribution to journalArticle

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Abstract

Aims The E143K (Glu → Lys) mutation in the myosin essential light chain has been associated with restrictive cardiomyopathy (RCM) in humans, but the mechanisms that underlie the development of defective cardiac function are unknown. Using transgenic E143K-RCM mice, we sought to determine the molecular and cellular triggers of E143K-induced heart remodelling. Methods and results The E143K-induced abnormalities in cardiac function and morphology observed by echocardiography and invasive haemodynamics were paralleled by augmented active and passive tension measured in skinned papillary muscle fibres compared with wild-type (WT)-generated force. In vitro, E143K-myosin had increased duty ratio and binding affinity to actin compared with WT-myosin, increased actin-activated ATPase activity and slower rates of ATP-dependent dissociation of the acto-myosin complex, indicating an E143K-induced myosin hypercontractility. E143K was also observed to reduce the level of myosin regulatory light chain phosphorylation while that of troponin-I remained unchanged. Small-angle X-ray diffraction data showed a decrease in the filament lattice spacing (d 1,0) with no changes in the equatorial reflections intensity ratios (I 1,1 /I 1,0) in E143K vs. WT skinned papillary muscles. The hearts of mutant-mice demonstrated ultrastructural defects and fibrosis that progressively worsened in senescent animals and these changes were hypothesized to contribute to diastolic disturbance and to mild systolic dysfunction. Gene expression profiles of E143K-hearts supported the histopathology results and showed an upregulation of stress-response and collagen genes. Finally, proteomic analysis evidenced RCM-dependent metabolic adaptations and higher energy demands in E143K vs. WT hearts. Conclusions As a result of the E143K-induced myosin hypercontractility, the hearts of RCM mice model exhibited cardiac dysfunction, stiff ventricles and physiological, morphologic, and metabolic remodelling consistent with the development of RCM. Future efforts should be directed toward normalization of myosin motor function and the use of myosin-specific therapeutics to avert the hypercontractile state of E143K-myosin and prevent pathological cardiac remodelling.

Original languageEnglish (US)
Pages (from-to)1124-1136
Number of pages13
JournalCardiovascular Research
Volume113
Issue number10
DOIs
StatePublished - Aug 1 2017

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Restrictive Cardiomyopathy
Ventricular Myosins
Myosin Light Chains
Myosins
Papillary Muscles
pioglitazone
Troponin I
Transcriptome
X-Ray Diffraction
Proteomics
Echocardiography
Actins
Fibrosis
Up-Regulation
Collagen
Adenosine Triphosphate
Hemodynamics
Phosphorylation

Keywords

  • Cardiac myosin essential light chain
  • Diastolic and systolic dysfunction
  • Hypercontractility
  • Myosin step size
  • Proteomics

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Hypercontractile mutant of ventricular myosin essential light chain leads to disruption of sarcomeric structure and function and results in restrictive cardiomyopathy in mice. / Yuan, Chen Ching; Kazmierczak, Katarzyna; Liang, Jingsheng; Kanashiro-Takeuchi, Rosemeire; Irving, Thomas C.; Gomes, Aldrin V; Wang, Yihua; Burghardt, Thomas P.; Szczesna-Cordary, Danuta.

In: Cardiovascular Research, Vol. 113, No. 10, 01.08.2017, p. 1124-1136.

Research output: Contribution to journalArticle

Yuan, CC, Kazmierczak, K, Liang, J, Kanashiro-Takeuchi, R, Irving, TC, Gomes, AV, Wang, Y, Burghardt, TP & Szczesna-Cordary, D 2017, 'Hypercontractile mutant of ventricular myosin essential light chain leads to disruption of sarcomeric structure and function and results in restrictive cardiomyopathy in mice', Cardiovascular Research, vol. 113, no. 10, pp. 1124-1136. https://doi.org/10.1093/cvr/cvx060
Yuan, Chen Ching ; Kazmierczak, Katarzyna ; Liang, Jingsheng ; Kanashiro-Takeuchi, Rosemeire ; Irving, Thomas C. ; Gomes, Aldrin V ; Wang, Yihua ; Burghardt, Thomas P. ; Szczesna-Cordary, Danuta. / Hypercontractile mutant of ventricular myosin essential light chain leads to disruption of sarcomeric structure and function and results in restrictive cardiomyopathy in mice. In: Cardiovascular Research. 2017 ; Vol. 113, No. 10. pp. 1124-1136.
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abstract = "Aims The E143K (Glu → Lys) mutation in the myosin essential light chain has been associated with restrictive cardiomyopathy (RCM) in humans, but the mechanisms that underlie the development of defective cardiac function are unknown. Using transgenic E143K-RCM mice, we sought to determine the molecular and cellular triggers of E143K-induced heart remodelling. Methods and results The E143K-induced abnormalities in cardiac function and morphology observed by echocardiography and invasive haemodynamics were paralleled by augmented active and passive tension measured in skinned papillary muscle fibres compared with wild-type (WT)-generated force. In vitro, E143K-myosin had increased duty ratio and binding affinity to actin compared with WT-myosin, increased actin-activated ATPase activity and slower rates of ATP-dependent dissociation of the acto-myosin complex, indicating an E143K-induced myosin hypercontractility. E143K was also observed to reduce the level of myosin regulatory light chain phosphorylation while that of troponin-I remained unchanged. Small-angle X-ray diffraction data showed a decrease in the filament lattice spacing (d 1,0) with no changes in the equatorial reflections intensity ratios (I 1,1 /I 1,0) in E143K vs. WT skinned papillary muscles. The hearts of mutant-mice demonstrated ultrastructural defects and fibrosis that progressively worsened in senescent animals and these changes were hypothesized to contribute to diastolic disturbance and to mild systolic dysfunction. Gene expression profiles of E143K-hearts supported the histopathology results and showed an upregulation of stress-response and collagen genes. Finally, proteomic analysis evidenced RCM-dependent metabolic adaptations and higher energy demands in E143K vs. WT hearts. Conclusions As a result of the E143K-induced myosin hypercontractility, the hearts of RCM mice model exhibited cardiac dysfunction, stiff ventricles and physiological, morphologic, and metabolic remodelling consistent with the development of RCM. Future efforts should be directed toward normalization of myosin motor function and the use of myosin-specific therapeutics to avert the hypercontractile state of E143K-myosin and prevent pathological cardiac remodelling.",
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author = "Yuan, {Chen Ching} and Katarzyna Kazmierczak and Jingsheng Liang and Rosemeire Kanashiro-Takeuchi and Irving, {Thomas C.} and Gomes, {Aldrin V} and Yihua Wang and Burghardt, {Thomas P.} and Danuta Szczesna-Cordary",
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T1 - Hypercontractile mutant of ventricular myosin essential light chain leads to disruption of sarcomeric structure and function and results in restrictive cardiomyopathy in mice

AU - Yuan, Chen Ching

AU - Kazmierczak, Katarzyna

AU - Liang, Jingsheng

AU - Kanashiro-Takeuchi, Rosemeire

AU - Irving, Thomas C.

AU - Gomes, Aldrin V

AU - Wang, Yihua

AU - Burghardt, Thomas P.

AU - Szczesna-Cordary, Danuta

PY - 2017/8/1

Y1 - 2017/8/1

N2 - Aims The E143K (Glu → Lys) mutation in the myosin essential light chain has been associated with restrictive cardiomyopathy (RCM) in humans, but the mechanisms that underlie the development of defective cardiac function are unknown. Using transgenic E143K-RCM mice, we sought to determine the molecular and cellular triggers of E143K-induced heart remodelling. Methods and results The E143K-induced abnormalities in cardiac function and morphology observed by echocardiography and invasive haemodynamics were paralleled by augmented active and passive tension measured in skinned papillary muscle fibres compared with wild-type (WT)-generated force. In vitro, E143K-myosin had increased duty ratio and binding affinity to actin compared with WT-myosin, increased actin-activated ATPase activity and slower rates of ATP-dependent dissociation of the acto-myosin complex, indicating an E143K-induced myosin hypercontractility. E143K was also observed to reduce the level of myosin regulatory light chain phosphorylation while that of troponin-I remained unchanged. Small-angle X-ray diffraction data showed a decrease in the filament lattice spacing (d 1,0) with no changes in the equatorial reflections intensity ratios (I 1,1 /I 1,0) in E143K vs. WT skinned papillary muscles. The hearts of mutant-mice demonstrated ultrastructural defects and fibrosis that progressively worsened in senescent animals and these changes were hypothesized to contribute to diastolic disturbance and to mild systolic dysfunction. Gene expression profiles of E143K-hearts supported the histopathology results and showed an upregulation of stress-response and collagen genes. Finally, proteomic analysis evidenced RCM-dependent metabolic adaptations and higher energy demands in E143K vs. WT hearts. Conclusions As a result of the E143K-induced myosin hypercontractility, the hearts of RCM mice model exhibited cardiac dysfunction, stiff ventricles and physiological, morphologic, and metabolic remodelling consistent with the development of RCM. Future efforts should be directed toward normalization of myosin motor function and the use of myosin-specific therapeutics to avert the hypercontractile state of E143K-myosin and prevent pathological cardiac remodelling.

AB - Aims The E143K (Glu → Lys) mutation in the myosin essential light chain has been associated with restrictive cardiomyopathy (RCM) in humans, but the mechanisms that underlie the development of defective cardiac function are unknown. Using transgenic E143K-RCM mice, we sought to determine the molecular and cellular triggers of E143K-induced heart remodelling. Methods and results The E143K-induced abnormalities in cardiac function and morphology observed by echocardiography and invasive haemodynamics were paralleled by augmented active and passive tension measured in skinned papillary muscle fibres compared with wild-type (WT)-generated force. In vitro, E143K-myosin had increased duty ratio and binding affinity to actin compared with WT-myosin, increased actin-activated ATPase activity and slower rates of ATP-dependent dissociation of the acto-myosin complex, indicating an E143K-induced myosin hypercontractility. E143K was also observed to reduce the level of myosin regulatory light chain phosphorylation while that of troponin-I remained unchanged. Small-angle X-ray diffraction data showed a decrease in the filament lattice spacing (d 1,0) with no changes in the equatorial reflections intensity ratios (I 1,1 /I 1,0) in E143K vs. WT skinned papillary muscles. The hearts of mutant-mice demonstrated ultrastructural defects and fibrosis that progressively worsened in senescent animals and these changes were hypothesized to contribute to diastolic disturbance and to mild systolic dysfunction. Gene expression profiles of E143K-hearts supported the histopathology results and showed an upregulation of stress-response and collagen genes. Finally, proteomic analysis evidenced RCM-dependent metabolic adaptations and higher energy demands in E143K vs. WT hearts. Conclusions As a result of the E143K-induced myosin hypercontractility, the hearts of RCM mice model exhibited cardiac dysfunction, stiff ventricles and physiological, morphologic, and metabolic remodelling consistent with the development of RCM. Future efforts should be directed toward normalization of myosin motor function and the use of myosin-specific therapeutics to avert the hypercontractile state of E143K-myosin and prevent pathological cardiac remodelling.

KW - Cardiac myosin essential light chain

KW - Diastolic and systolic dysfunction

KW - Hypercontractility

KW - Myosin step size

KW - Proteomics

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