Discrete effects of A57G-myosin essential light chain mutation associated with familial hypertrophic cardiomyopathy

Katarzyna Kazmierczak, Ellena C. Paulino, Wenrui Huang, Priya Muthu, Jingsheng Liang, Chen Ching Yuan, Ana I. Rojas, Joshua Hare, Danuta Szczesna-Cordary

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

The functional consequences of the familial hypertrophic cardiomyopathy A57G (alanine-to-glycine) mutation in the myosin ventricular essential light chain (ELC) were assessed in vitro and in vivo using previously generated transgenic (Tg) mice expressing A57G-ELC mutant vs. wild-type (WT) of human cardiac ELC and in recombinant A57G- or WT-protein-exchanged porcine cardiac muscle strips. Compared with the Tg-WT, there was a significant increase in the Ca2+ sensitivity of force (ΔpCa50 ≅ 0.1) and an ~1.3-fold decrease in maximal force per cross section of muscle observed in the mutant preparations. In addition, a significant increase in passive tension in response to stretch was monitored in Tg-A57G vs. Tg-WT strips indicating a mutation-induced myocardial stiffness. Consistently, the hearts of Tg-A57G mice demonstrated a high level of fibrosis and hypertrophy manifested by increased heart weight-to-body weight ratios and a decreased number of nuclei indicating an increase in the two-dimensional size of Tg-A57G vs. Tg-WT myocytes. Echocardiography examination showed a phenotype of eccentric hypertrophy in Tg-A57G mice, enhanced left ventricular (LV) cavity dimension without changes in LV posterior/anterior wall thickness. Invasive hemodynamics data revealed significantly increased end-systolic elastance, defined by the slope of the pressure-volume relationship, indicating a mutation-induced increase in cardiac contractility. Our results suggest that the A57G allele causes disease by means of a discrete modulation of myofilament function, increased Ca2+ sensitivity, and decreased maximal tension followed by compensatory hypertrophy and enhanced contractility. These and other contributing factors such as increased myocardial stiffness and fibrosis most likely activate cardiomyopathic signaling pathways leading to pathologic cardiac remodeling.

Original languageEnglish
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume305
Issue number4
DOIs
StatePublished - May 8 2013

Fingerprint

Familial Hypertrophic Cardiomyopathy
Myosin Light Chains
Hypertrophy
Transgenic Mice
Mutation
Fibrosis
Light
Myofibrils
Alanine
Glycine
Muscle Cells
Echocardiography
Myocardium
Swine
Hemodynamics
Alleles
Body Weight
Phenotype
Pressure
Weights and Measures

Keywords

  • Ca sensitivity of contraction
  • Echocardiography
  • Hypertrophic cardiomyopathy
  • Myosin essential light chain
  • Pressure-volume loops

ASJC Scopus subject areas

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

Cite this

Discrete effects of A57G-myosin essential light chain mutation associated with familial hypertrophic cardiomyopathy. / Kazmierczak, Katarzyna; Paulino, Ellena C.; Huang, Wenrui; Muthu, Priya; Liang, Jingsheng; Yuan, Chen Ching; Rojas, Ana I.; Hare, Joshua; Szczesna-Cordary, Danuta.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 305, No. 4, 08.05.2013.

Research output: Contribution to journalArticle

Kazmierczak, Katarzyna ; Paulino, Ellena C. ; Huang, Wenrui ; Muthu, Priya ; Liang, Jingsheng ; Yuan, Chen Ching ; Rojas, Ana I. ; Hare, Joshua ; Szczesna-Cordary, Danuta. / Discrete effects of A57G-myosin essential light chain mutation associated with familial hypertrophic cardiomyopathy. In: American Journal of Physiology - Heart and Circulatory Physiology. 2013 ; Vol. 305, No. 4.
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AU - Huang, Wenrui

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AU - Liang, Jingsheng

AU - Yuan, Chen Ching

AU - Rojas, Ana I.

AU - Hare, Joshua

AU - Szczesna-Cordary, Danuta

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