scholarly journals Kinetics of a single cross-bridge in familial hypertrophic cardiomyopathy heart muscle measured by reverse Kretschmann fluorescence

2010 ◽  
Vol 15 (1) ◽  
pp. 017011 ◽  
Author(s):  
Prasad Mettikolla ◽  
Nils Calander ◽  
Rafal Luchowski ◽  
Ignacy Gryczynski ◽  
Zygmunt Gryczynski ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Heart Muscle ◽  
Familial Hypertrophic Cardiomyopathy ◽  
Cross Bridge ◽  
Single Cross ◽  
Kinetics Of

Single Molecule Detection Approach to Muscle Study: Kinetics of a Single Cross-Bridge During Contraction of Muscle

2012 ◽  
pp. 311-334 ◽  
Author(s):  
Julian Borejdo ◽  
Danuta Szczesna-Cordary ◽  
Priya Muthu ◽  
Prasad Metticolla ◽  
Rafal Luchowski ◽  
...  
Keyword(s):  
Single Molecule ◽  
Single Molecule Detection ◽  
Cross Bridge ◽  
Detection Approach ◽  
Single Cross ◽  
Kinetics Of

scholarly journals Impact of familial hypertrophic cardiomyopathy-linked mutations in the NH2 terminus of the RLC on β-myosin cross-bridge mechanics

2014 ◽  
Vol 117 (12) ◽  
pp. 1471-1477 ◽  
Author(s):  
Gerrie P. Farman ◽  
Priya Muthu ◽  
Katarzyna Kazmierczak ◽  
Danuta Szczesna-Cordary ◽  
Jeffrey R. Moore
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Familial Hypertrophic Cardiomyopathy ◽  
Sarcomeric Proteins ◽  
Motion Generation ◽  
In Vitro Motility Assay ◽  
In Vitro Motility ◽  
Cross Bridge ◽  
Significant Difference ◽  
The Impact

Familial hypertrophic cardiomyopathy (HCM) is associated with mutations in sarcomeric proteins, including the myosin regulatory light chain (RLC). Here we studied the impact of three HCM mutations located in the NH2 terminus of the RLC on the molecular mechanism of β-myosin heavy chain (MHC) cross-bridge mechanics using the in vitro motility assay. To generate mutant β-myosin, native RLC was depleted from porcine cardiac MHC and reconstituted with mutant (A13T, F18L, and E22K) or wild-type (WT) human cardiac RLC. We characterized the mutant myosin force and motion generation capability in the presence of a frictional load. Compared with WT, all three mutants exhibited reductions in maximal actin filament velocity when tested under low or no frictional load. The actin-activated ATPase showed no significant difference between WT and HCM-mutant-reconstituted myosins. The decrease in velocity has been attributed to a significantly increased duty cycle, as was measured by the dependence of actin sliding velocity on myosin surface density, for all three mutant myosins. These results demonstrate a mutation-induced alteration in acto-myosin interactions that may contribute to the pathogenesis of HCM.

scholarly journals Cross-bridge kinetics in myofibrils containing familial hypertrophic cardiomyopathy R58Q mutation in the regulatory light chain of myosin

2011 ◽  
Vol 284 (1) ◽  
pp. 71-81 ◽  
Author(s):  
P. Mettikolla ◽  
N. Calander ◽  
R. Luchowski ◽  
I. Gryczynski ◽  
Z. Gryczynski ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Light Chain ◽  
Regulatory Light Chain ◽  
Familial Hypertrophic Cardiomyopathy ◽  
Cross Bridge

scholarly journals Impact of Familial Hypertrophic Cardiomyopathy-Linked Mutations in the N-Terminus of the RLC on β-Myosin Cross-Bridge Mechanics

2013 ◽  
Vol 104 (2) ◽  
pp. 157a
Author(s):  
Gerrie P. Farman ◽  
Priya Mutha ◽  
Katarzyna Kazmierczak ◽  
Danuta Szczesna-Cordary ◽  
Jeffery R. Moore
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Familial Hypertrophic Cardiomyopathy ◽  
Cross Bridge ◽  
N Terminus

E22K mutation of RLC that causes familial hypertrophic cardiomyopathy in heterozygous mouse myocardium: effect on cross-bridge kinetics

2006 ◽  
Vol 291 (5) ◽  
pp. H2098-H2106 ◽  
Author(s):  
D. Dumka ◽  
J. Talent ◽  
I. Akopova ◽  
G. Guzman ◽  
D. Szczesna-Cordary ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Light Chain ◽  
Left Ventricular ◽  
Familial Hypertrophic Cardiomyopathy ◽  
Time Resolved ◽  
Essential Light Chain ◽  
Cross Bridge ◽  
The Difference ◽  
Cross Bridges ◽  
The Times

Familial hypertrophic cardiomyopathy is a disease characterized by left ventricular and/or septal hypertrophy and myofibrillar disarray. It is caused by mutations in sarcomeric proteins, including the ventricular isoform of myosin regulatory light chain (RLC). The E22K mutation is located in the RLC Ca2+-binding site. We have studied transgenic (Tg) mouse cardiac myofibrils during single-turnover contraction to examine the influence of E22K mutation on 1) dissociation time (τ1) of myosin heads from thin filaments, 2) rebinding time (τ2) of the cross bridges to actin, and 3) dissociation time (τ3) of ADP from the active site of myosin. τ1 was determined from the increase in the rate of rotation of actin monomer to which a cross bridge was bound. τ2 was determined from the rate of anisotropy change of the recombinant essential light chain of myosin labeled with rhodamine exchanged for native light chain (LC1) in the cardiac myofibrils. τ3 was determined from anisotropy of muscle preloaded with a stoichiometric amount of fluorescent ADP. Cross bridges were induced to undergo a single detachment-attachment cycle by a precise delivery of stoichiometric ATP from a caged precursor. The times were measured in Tg-mutated (Tg-m) heart myofibrils overexpressing the E22K mutation of human cardiac RLC. Tg wild-type (Tg-wt) and non-Tg muscles acted as controls. τ1 was statistically greater in Tg-m than in controls. τ2 was shorter in Tg-m than in non-Tg, but the same as in Tg-wt. τ3 was the same in Tg-m and controls. To determine whether the difference in τ1 was due to intrinsic difference in myosin, we estimated binding of Tg-m and Tg-wt myosin to fluorescently labeled actin by measuring fluorescent lifetime and time-resolved anisotropy. No difference in binding was observed. These results suggest that the E22K mutation has no effect on mechanical properties of cross bridges. The slight increase in τ1 was probably caused by myofibrillar disarray. The decrease in τ2 of Tg hearts was probably caused by replacement of the mouse RLC for the human isoform in the Tg mice.

scholarly journals N-acetylcysteine reverses diastolic dysfunction and hypertrophy in familial hypertrophic cardiomyopathy

2015 ◽  
Vol 309 (10) ◽  
pp. H1720-H1730 ◽  
Author(s):  
Tanganyika Wilder ◽  
David M. Ryba ◽  
David F. Wieczorek ◽  
Beata M. Wolska ◽  
R. John Solaro
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Diastolic Dysfunction ◽  
Diastolic Function ◽  
Familial Hypertrophic Cardiomyopathy ◽  
Cross Bridge ◽  
Myosin Binding Protein ◽  
Myosin Binding Protein C ◽  
Plasmic Reticulum ◽  
Extracellular Signal ◽  
Tension Cost

S-glutathionylation of cardiac myosin-binding protein C (cMyBP-C) induces Ca2+ sensitization and a slowing of cross-bridge kinetics as a result of increased oxidative signaling. Although there is evidence for a role of oxidative stress in disorders associated with hypertrophic cardiomyopathy (HCM), this mechanism is not well understood. We investigated whether oxidative myofilament modifications may be in part responsible for diastolic dysfunction in HCM. We administered N-acetylcysteine (NAC) for 30 days to 1-mo-old wild-type mice and to transgenic mice expressing a mutant tropomyosin (Tm-E180G) and nontransgenic littermates. Tm-E180G hearts demonstrate a phenotype similar to human HCM. After NAC administration, the morphology and diastolic function of Tm-E180G mice was not significantly different from controls, indicating that NAC had reversed baseline diastolic dysfunction and hypertrophy in our model. NAC administration also increased sarco(endo)plasmic reticulum Ca2+ ATPase protein expression, reduced extracellular signal-related kinase 1/2 phosphorylation, and normalized phosphorylation of phospholamban, as assessed by Western blot. Detergent-extracted fiber bundles from NAC-administered Tm-E180G mice showed nearly nontransgenic (NTG) myofilament Ca2+ sensitivity. Additionally, we found that NAC increased tension cost and rate of cross-bridge reattachment. Tm-E180G myofilaments were found to have a significant increase in S-glutathionylation of cMyBP-C, which was returned to NTG levels upon NAC administration. Taken together, our results indicate that oxidative myofilament modifications are an important mediator in diastolic function, and by relieving this modification we were able to reverse established diastolic dysfunction and hypertrophy in HCM.

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