What is the clinical evidence from this study?

Population: Hypertrophic cardiomyopathy (HCM). Intervention: R403Q mutation in human β-cardiac myosin vs. Wild type human β-cardiac myosin. Primary outcome: In vitro contractility parameters (intrinsic force, unloaded velocity, ATPase activity).

What question did this study set out to answer?

To determine the molecular mechanism and contractility effects of the hypertrophic cardiomyopathy-associated R403Q mutation using recombinant human β-cardiac myosin.

October 2, 2015Science AdvancesOpen Access

Contractility parameters of human β-cardiac myosin with the hypertrophic cardiomyopathy mutation R403Q show loss of motor function

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Key result

R403Q mutation in β-cardiac myosin reduces intrinsic force ~15% and ATPase activity versus wild type.

Population

Recombinant human β-cardiac myosin (in vitro model)

Comparison

R403Q mutation vs Wild type human β-cardiac myosin

Design

Preclinical

Authors

SNSuman NagBristol-Myers Squibb (Germany)RSRuth F. SommesePfizer (United States)ZUZoltán UjfalusiUniversity of Pecs

Discussion

Member takes

Implication

Hypothesis-generating for HCM mechanisms; leaves open translation to human disease or therapies.

Key Points

To determine the molecular mechanism and contractility effects of the hypertrophic cardiomyopathy-associated R403Q mutation using recombinant human β-cardiac myosin.
Expressed and purified recombinant human wild-type and R403Q β-cardiac myosin motor domains.
Characterized in vitro contractility parameters, unloaded velocity, and load-dependent velocity using both pure actin filaments and regulated actin filaments containing tropomyosin and troponin.
Measured actin-activated adenosine triphosphatase (ATPase) activity under calcium regulation.
With pure actin filaments, R403Q myosin generated ~15% lower intrinsic force and had ~10% higher unloaded velocity than wild type, leading to reduced contractility under high external loads.
With regulated actin filaments, R403Q myosin demonstrated lower contractility than wild type across all loads and showed no increase in unloaded velocity.
Actin-activated ATPase activity for R403Q myosin was ~30% lower than wild type in the presence of calcium-regulated actin filaments, predicting a lower unloaded duty ratio.

Structured PICO

Population

Recombinant human β-cardiac myosin (in vitro model)

Intervention

R403Q mutation

Comparator

Wild type human β-cardiac myosin

Outcome

In vitro contractility parameters (intrinsic force, unloaded velocity, actin-activated ATPase activity)surrogate

The R403Q mutation in human β-cardiac myosin results in a loss of motor function and contractility in vitro, providing mechanistic insight into hypertrophic cardiomyopathy.

Cite This Study

Nag et al. (2015) studied Hypertrophic cardiomyopathy (HCM). R403Q mutation in human β-cardiac myosin vs. Wild type human β-cardiac myosin was evaluated on In vitro contractility parameters (intrinsic force, unloaded velocity, ATPase activity). The R403Q mutation in human β-cardiac myosin resulted in a ~15% lower intrinsic force and ~30% lower actin-activated ATPase activity with regulated actin filaments compared to wild type.

synapsesocial.com/papers/6a08db2b02034f20cae4ab99 https://doi.org/10.1126/sciadv.1500511

Topics

Hypertrophic cardiomyopathy

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Contractility parameters of human β-cardiac myosin with the hypertrophic cardiomyopathy mutation R403Q show loss of motor function

Discussion

Member takes

Implication

Key Points

Structured PICO

Cite This Study

Topics

Contractility parameters of human β-cardiac myosin with the hypertrophic cardiomyopathy mutation R403Q show loss of motor function

Discussion

Member takes

Implication

Key Points

Structured PICO

Cite This Study

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