November 6, 2010Journal of Biological ChemistryOpen Access

Strong Cross-bridges Potentiate the Ca2+ Affinity Changes Produced by Hypertrophic Cardiomyopathy Cardiac Troponin C Mutants in Myofilaments

Q: What is the clinical evidence from this study?

Study design: Other. Population: Hypertrophic Cardiomyopathy. Intervention: HCM-cTnC mutants (A8V, D145E, E134D) vs. Wild-type (WT) cTnC. Primary outcome: Ca2+ dissociation rate (koff) and apparent Ca2+ affinity (pCa50).

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Key result

Strong cross-bridges potentiate the Ca2+-sensitizing effect of HCM-cTnC mutants (A8V and D145E) on the myofilament, leading to a slower Ca2+ dissociation rate that correlates with diastolic dysfunction.

Population

Reconstituted thin filaments and skinned porcine papillary fibers containing wild-type or hypertrophic…

Comparison

Addition of myosin subfragment 1 in the absence… vs Wild-type cTnC and conditions without S1 or with…

Design

Preclinical

Authors

JPJosé R. PintoHeart Failure / Cardiomyopathy DRDaniel P. ReynaldoUniversidade Federal do Rio de Janeiro MPMichelle S. ParvatiyarHeart Failure / Cardiomyopathy

Discussion

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Implication

Animal models link cross-bridge potentiation to HCM diastolic dysfunction; leaves open clinical relevance pending human validation.

Structured PICO

Population

In vitro biochemical study examining the steady-state and kinetic parameters of hypertrophic cardiomyopathy-cardiac troponin C (HCM-cTnC) mutants in myofilaments.

Intervention

Addition of myosin subfragment 1 (S1) in the absence of MgATP2- (condition conducive to rigor cross-bridge formation).

Comparator

Wild-type (WT) cTnC and conditions without S1 or with MgATP2-.

Outcome

Apparent Ca2+ affinity (pCa50) and kinetics of Ca2+ dissociation (koff).surrogate

Strong cross-bridges potentiate the calcium-sensitizing effects of HCM-associated cTnC mutants (A8V and D145E), slowing calcium dissociation and providing a molecular basis for the diastolic dysfunction observed in HCM patients.

Limitations

Reconstituted in vitro systems lack the ability to modify the regulation of transcription factors involved in the hypertrophic signaling pathway.
In vitro systems prevent observing differences due to changes in Ca2+ handling, protein isoform switching, and cardiac hypertrophy in vivo.
Reconstituted systems lack the ability to modify transcription factors involved in hypertrophic signaling
Cannot observe differences due to changes in Ca2+ handling, protein isoform switching, cardiac hypertrophy, and diastolic function in vivo

Cite This Study

Pinto et al. (2010) studied Hypertrophic Cardiomyopathy. HCM-cTnC mutants (A8V, D145E, E134D) vs. Wild-type (WT) cTnC was evaluated on Ca2+ dissociation rate (koff) and apparent Ca2+ affinity (pCa50). Strong cross-bridges potentiate the Ca2+-sensitizing effect of HCM-cTnC mutants (A8V and D145E) on the myofilament, leading to a slower Ca2+ dissociation rate that correlates with diastolic dysfunction.

synapsesocial.com/papers/6a8843e033299ecf904fd551 https://doi.org/10.1074/jbc.m110.168583

Topics

Hypertrophic cardiomyopathy

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Strong Cross-bridges Potentiate the Ca2+ Affinity Changes Produced by Hypertrophic Cardiomyopathy Cardiac Troponin C Mutants in Myofilaments

Discussion

Member takes

Implication

Structured PICO

Limitations

Cite This Study

Topics

Strong Cross-bridges Potentiate the Ca2+ Affinity Changes Produced by Hypertrophic Cardiomyopathy Cardiac Troponin C Mutants in Myofilaments

Discussion

Member takes

Implication

Structured PICO

Limitations

Cite This Study

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