What question did this study set out to answer?

To determine how myosin motor activation is regulated across the cardiac cycle and investigate the structural basis of length-dependent activation underlying the Frank-Starling mechanism.

March 6, 2017Proceedings of the National Academy of Sciences

Myosin filament activation in the heart is tuned to the mechanical task

Q: What is the clinical evidence from this study?

Study design: Other. Population: Normal cardiac physiology (n=4). Intervention: Sarcomere length control (Length Clamp vs Fixed End) vs. Diastole / alternative loading conditions. Primary outcome: Fraction of myosin motors leaving the off state and attached to actin during systole.

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Key result

The number of myosin motors recruited from the off state during systole is proportional to the sarcomere length-dependent systolic force, revealing a thick filament mechanosensing mechanism underlying the Frank-Starling law.

Population

Intact ventricular trabeculae from rats

Design

Preclinical

Authors

MRMassimo ReconditiUniversity of Florence MCMarco CaremaniSynlab Czech (Czechia)FPFrancesca PinzautiUniversity of Florence

Discussion

Member takes

Implication

Provides a novel molecular target for heart failure therapeutics; extends fundamental understanding of the Frank-Star.

Key Points

To determine how myosin motor activation is regulated across the cardiac cycle and investigate the structural basis of length-dependent activation underlying the Frank-Starling mechanism.
Mounted intact ventricular trabeculae from rats under precise sarcomere length control during diastole-systole cycles.
Combined sarcomere mechanics with micrometer-to-nanometer-scale synchrotron X-ray diffraction to track the axial movement of myosin motors in real time.
Myosin motors transition out of the inactive, ATP-conserving 'off' state in numbers directly proportional to sarcomere length-dependent systolic force.
Mechanosensing within the thick filament dynamically tunes the metabolic cost of systole to the mechanical workload.
Disruption of the intermolecular and intramolecular interactions that stabilize the myosin 'off' state represents a putative pathway for cardiomyopathy mutations.

Structured PICO

Population

Intact right ventricular trabeculae from male rats used to study sarcomere mechanics and X-ray diffraction during the diastole-systole cycle.

Intervention

Sarcomere length control and measurement of axial movement of myosin motors using micrometer-nanometer-scale X-ray diffraction from synchrotron light

Outcome

Axial movement of myosin motors and the number of myosin motors leaving the off state during the diastole-systole cyclesurrogate

Mechanosensing-based regulation of the thick filament adjusts the energetic cost of systole to the mechanical task, revealing a key molecular aspect of the Frank-Starling mechanism.

Limitations

Use of an animal model (rat trabeculae) rather than human tissue
In vitro experimental conditions may not fully replicate in vivo whole-heart dynamics
Extrapolation to human cardiomyopathy mechanisms remains putative

Cite This Study

Reconditi et al. (2017) studied Normal cardiac physiology (n=4). Sarcomere length control (Length Clamp vs Fixed End) vs. Diastole / alternative loading conditions was evaluated on Fraction of myosin motors leaving the off state and attached to actin during systole. The number of myosin motors recruited from the off state during systole is proportional to the sarcomere length-dependent systolic force, revealing a thick filament mechanosensing mechanism underlying the Frank-Starling law.

synapsesocial.com/papers/6a86da31240d988a48a23ba2 https://doi.org/10.1073/pnas.1619484114

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Myosin filament activation in the heart is tuned to the mechanical task

Discussion

Member takes

Implication

Key Points

Structured PICO

Limitations

Cite This Study

Myosin filament activation in the heart is tuned to the mechanical task

Discussion

Member takes

Implication

Key Points

Structured PICO

Limitations

Cite This Study

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