What question did this study set out to answer?

To determine the molecular and mechanical mechanism by which familial hypertrophic cardiomyopathy mutations in the myosin regulatory light chain disrupt cardiac myosin function.

September 20, 2010Proceedings of the National Academy of SciencesOpen Access

Cardiomyopathy-linked myosin regulatory light chain mutations disrupt myosin strain-dependent biochemistry

Q: What is the clinical evidence from this study?

Study design: Other. Population: Familial hypertrophic cardiomyopathy (FHC). Intervention: R58Q and N47K mutations in myosin regulatory light chain vs. Wild-type (WT) or native myosin. Primary outcome: Isometric force and power output (p=<0.001).

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Key result

FHC-linked R58Q and N47K mutations in the myosin regulatory light chain significantly reduced isometric force and power output compared with wild-type myosin due to a loss of strain sensitivity.

Population

Native porcine cardiac myosin exchanged with recombinant human ventricular wild type (WT) or FHC mutant RLC

Comparison

FHC mutant RLC (R58Q and N47K) vs Recombinant human ventricular wild type or…

Design

Preclinical

Authors

MGMichael J. GreenbergWashington University in St. Louis KKKatarzyna KaźmierczakHeart Failure / Cardiomyopathy DSDanuta Szczesna‐CordaryHeart Failure / Cardiomyopathy

Discussion

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Implication

May impair contractility in FHC models; hypothesis-generating and should not yet change practice or guide human research.

Key Points

To determine the molecular and mechanical mechanism by which familial hypertrophic cardiomyopathy mutations in the myosin regulatory light chain disrupt cardiac myosin function.
Replaced endogenous regulatory light chain (RLC) from native porcine cardiac myosin with recombinant human ventricular wild-type or mutant (R58Q and N47K) RLC.
Measured actin filament sliding velocity, force, and power output under both loaded and unloaded conditions using an in vitro motility assay.
Unloaded actin filament sliding speeds showed no differences between mutant myosins and wild-type or native controls.
Both R58Q and N47K mutants produced lower force and power output relative to wild-type controls under mechanical load.
Loaded functional deficits were driven by a mutation-induced loss of myosin strain sensitivity toward ADP affinity, indicating mechanical changes in the myosin neck.

Structured PICO

Population

Native porcine cardiac myosin exchanged with recombinant human ventricular wild type (WT) or FHC mutant RLC

Intervention

FHC mutant RLC (R58Q and N47K)

Comparator

Recombinant human ventricular wild type (WT) or native myosin

Outcome

Ability of the reconstituted myosin to propel actin filament sliding (force and power output, loaded kinetics)surrogate

Main Result

p-value: p=<0.001

FHC mutations R58Q and N47K in the myosin regulatory light chain alter the mechanical properties of the myosin neck region, leading to reduced force and power output.

Limitations

In vitro model may not fully capture in vivo physiology
Species-to-species variations in cardiac contractility and MHC isoform distribution may affect interpretation
Several physical constants in the frictional loading model are poorly defined, affecting absolute values

Cite This Study

Greenberg et al. (2010) studied Familial hypertrophic cardiomyopathy (FHC). R58Q and N47K mutations in myosin regulatory light chain vs. Wild-type (WT) or native myosin was evaluated on Isometric force and power output (p=<0.001). FHC-linked R58Q and N47K mutations in the myosin regulatory light chain significantly reduced isometric force and power output compared with wild-type myosin due to a loss of strain sensitivity.

synapsesocial.com/papers/6a7b9c934fcef545fadf7969 https://doi.org/10.1073/pnas.1009619107

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Cardiomyopathy-linked myosin regulatory light chain mutations disrupt myosin strain-dependent biochemistry

Discussion

Member takes

Implication

Key Points

Structured PICO

Main Result

Limitations

Cite This Study

Cardiomyopathy-linked myosin regulatory light chain mutations disrupt myosin strain-dependent biochemistry

Discussion

Member takes

Implication

Key Points

Structured PICO

Main Result

Limitations

Cite This Study

Also Consider

Also Consider