Structural and functional aspects of the myosin essential light chain in cardiac muscle contraction

Muthu, Priya; Wang, Li; Yuan, Chen; Kazmierczak, Katarzyna; Huang, Wenrui; Hernandez, Olga M.; Kawai, Masataka; Irving, Thomas C.; Szczesna‐Cordary, Danuta

doi:10.1096/fj.11-191973

Cited by 48 publications

(98 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In line with our data, a hypertrophic cardiac phenotype could neither be observed in a homologous rabbit model which overexpressed M149V mutated rabbit VLC-1 [18] nor in the homologous TgM model which overexpressed M149V mutated mouse VLC-1 [19]. Likewise, a heterologous TgM model overexpressing A57G mutated hVLC-1 (TgM A57G ) did not develop the hypertrophic phenotype [20]. In line, stroke volume, ejection fraction, and fractional shortening were similar in TgM E56G , TgM hVLC-1 , and C57BL/6 (Supplement data, Table 1).…”

Section: Resultssupporting

confidence: 83%

See 1 more Smart Citation

Molecular mechanism regulating myosin and cardiac functions by ELC

Lossie

Köhncke

Mahmoodzadeh

et al. 2014

Biochemical and Biophysical Research Communications

View full text Add to dashboard Cite

The essential myosin light chain (ELC) is involved in modulation of force generation of myosin motors and cardiac contraction, while its mechanism of action remains elusive. We hypothesized that ELC could modulate myosin stiffness which subsequently determines its force production and cardiac contraction. We therefore generated heterologous transgenic mouse (TgM) strains with cardiomyocyte-specific expression of ELC with human ventricular ELC (hVLC-1; TgM hVLC-1 ) or E56G-mutated hVLC-1 (hVLC-1 E56G ; TgM E56G ). hVLC-1 or hVLC-1 E56G expression in TgM was around 39% and 41%, respectively of total VLC-1. Laser trap and in vitro motility assays showed that stiffness and actin sliding velocity of myosin with hVLC-1 prepared from TgM hVLC-1 (1.67pN/nm and 2.3µm/s, respectively) were significantly higher than myosin with hVLC-1 E56G prepared from TgM E56G (1.25pN/nm and 1.7µm/s, respectively) or myosin with mouse VLC-1 (mVLC-1) prepared from C57/BL6 (1.41 pN/nm and 1.5±0.03 µm/s , respectively). Maximal left ventricular pressure development of isolated perfused hearts in vitro prepared from TgM hVLC-1 (80.0mmHg) were significantly higher than hearts from TgM E56G (66.2mmHg) or C57/BL6 (59.3±3.9 mmHg). These findings show that ELCs decreased myosin stiffness, in vitro motility, and thereby cardiac functions in the order hVLC-1 > hVLC-1 E56G ≈ mVLC-1. They also suggest a molecular pathomechanism of cardiomyopathies caused by hVLC-1 mutations.

show abstract

Section: Resultssupporting

confidence: 83%

“…This predicts a "loss of function" of myosin with hVLC-1 A57G similar to the myosin with hVLC-1 E56G investigated herein and, therefore decreased stiffness. By contrast myosin stiffness of TgM A57G rose [20], indicating a "gain of function" of myosin with hVLC-1 A57G . The reason for this discrepancy is yet unknown.…”

Section: Resultsmentioning

confidence: 87%

Molecular mechanism regulating myosin and cardiac functions by ELC

Lossie

Köhncke

Mahmoodzadeh

et al. 2014

Biochemical and Biophysical Research Communications

View full text Add to dashboard Cite

show abstract

“…The equatorial X-ray diffraction patterns were collected from freshly skinned Tg papillary muscle strips using a small-angle instrument on the BioCAT beamline 18ID (Advanced Photon Source, Argonne National Laboratory). The distance between the 1,0 and 1,1 reflections allowed the assessment of the interfilament lattice spacing (21). Intensities of the 1,0 and 1,1 reflections were determined from nonlinear least square fits to 1D intensity projections along the equator.…”

Section: Methodsmentioning

confidence: 99%

“…Fig. 5 represents the cross-bridge mass distribution between the thick and thin filaments, as indicated by the ratio (I 1,1 /I 1,0, ) of the intensity of the 1,1 to that of the 1,0 equatorial reflections (21). Both IFS and I 1,1 /I 1,0 were significantly higher in D166V mice compared with WT.…”

Section: Myocardium (mentioning

confidence: 99%

Constitutive phosphorylation of cardiac myosin regulatory light chain prevents development of hypertrophic cardiomyopathy in mice

Yuan

Muthu

Kazmierczak

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

127

View full text Add to dashboard Cite

Myosin light chain kinase (MLCK)-dependent phosphorylation of the regulatory light chain (RLC) of cardiac myosin is known to play a beneficial role in heart disease, but the idea of a phosphorylation-mediated reversal of a hypertrophic cardiomyopathy (HCM) phenotype is novel. Our previous studies on transgenic (Tg) HCM-RLC mice revealed that the D166V (Aspartate166 →Valine) mutation-induced changes in heart morphology and function coincided with largely reduced RLC phosphorylation in situ. We hypothesized that the introduction of a constitutively phosphorylated Serine15 (S15D) into the hearts of D166V mice would prevent the development of a deleterious HCM phenotype. In support of this notion, MLCK-induced phosphorylation of D166V-mutated hearts was found to rescue some of their abnormal contractile properties. Tg-S15D-D166V mice were generated with the human cardiac RLC-S15D-D166V construct substituted for mouse cardiac RLC and were subjected to functional, structural, and morphological assessments. The results were compared with Tg-WT and Tg-D166V mice expressing the human ventricular RLC-WT or its D166V mutant, respectively. Echocardiography and invasive hemodynamic studies demonstrated significant improvements of intact heart function in S15D-D166V mice compared with D166V, with the systolic and diastolic indices reaching those monitored in WT mice. A largely reduced maximal tension and abnormally high myofilament Ca 2+ sensitivity observed in D166V-mutated hearts were reversed in S15D-D166V mice. Lowangle X-ray diffraction study revealed that altered myofilament structures present in HCM-D166V mice were mitigated in S15D-D166V rescue mice. Our collective results suggest that expression of pseudophosphorylated RLC in the hearts of HCM mice is sufficient to prevent the development of the pathological HCM phenotype.cardiomyopathy | hemodynamics | myocardial contraction | X-ray structure | myosin RLC

show abstract

“…A wealth of evidence suggests that it may play a role in force development and muscle contraction (17,24,36,40,54). The functional importance of myosin ELC in cardiac muscle has emerged through the identification of several mutations in the ELC gene (MYL3) shown to cause familial hypertrophic cardiomyopathy (FHC).…”

mentioning

confidence: 99%

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

Kazmierczak

Paulino

Huang

et al. 2013

American Journal of Physiology-Heart and Circulatory Physiology

Self Cite

View full text Add to dashboard Cite

(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 Ca 2ϩ sensitivity of force (⌬pCa50 Х 0.1) and an ϳ1.3-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 Ca 2ϩ 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. myosin essential light chain; hypertrophic cardiomyopathy; Ca 2ϩ sensitivity of contraction; echocardiography; pressure-volume loops THE BEATING OF THE HEART DEPENDS on ATP-controlled synchronous interactions between two major contractile proteins; myosin and actin (15). The myosin cross bridges are the molecular motors of the heart, which bind and hydrolyze Mg-ATP and cyclically attach and dissociate from actin-tropomyosin (Tm)-troponin (Tn) thin filaments in a Ca 2ϩ -dependent manner. The cycle of Ca 2ϩ fluxes regulate the coupling between excitation and contraction and permit the highly synchronized action of cardiac sarcomeres causing the heart to contract (systole) or relax (diastole) (20). The two key components of the myosin cross bridge include the motor domain, consisting of the ATP and actin binding sites, and the neck domain also called the lever arm, which is structurally supported by two types of myosin light chains, the essential (ELC) and the regulatory (RLC) light chains (44). Attached to their respective IQ motifs on the myosin heavy chain (MHC), both light chains inherently participate in all biochemical steps of the acto-myosin cycle and execution of the power stroke (52). As components of the neck region of myosin, both ELC and RL...

show abstract

Structural and functional aspects of the myosin essential light chain in cardiac muscle contraction

Cited by 48 publications

References 49 publications

Molecular mechanism regulating myosin and cardiac functions by ELC

Molecular mechanism regulating myosin and cardiac functions by ELC

Constitutive phosphorylation of cardiac myosin regulatory light chain prevents development of hypertrophic cardiomyopathy in mice

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

Contact Info

Product

Resources

About