What is the clinical evidence from this study?

Study design: Other. Population: Hypertrophic cardiomyopathy. Intervention: cTnI(R146G) and cTnI(R21C) mutations vs. cTnI(WT). Primary outcome: Contractile activation and relaxation kinetics and response to PKA.

What does this research mean for the field?

Hypertrophic cardiomyopathy-associated mutations cTnI(R146G) and cTnI(R21C) blunt PKA modulation of cardiac activation and relaxation kinetics by prohibiting the interaction between the cardiac-specific N-terminus and the cTnI inhibitory peptide. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

September 22, 2015Journal of Biological ChemistryOpen Access

Troponin I Mutations R146G and R21C Alter Cardiac Troponin Function, Contractile Properties, and Modulation by Protein Kinase A (PKA)-mediated Phosphorylation

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Key result

Hypertrophic cardiomyopathy-associated mutations cTnI(R146G) and cTnI(R21C) blunted PKA modulation of activation and relaxation kinetics by prohibiting cardiac-specific N-terminal interaction.

Population

Rat ventricular myofibrils and molecular dynamics simulations modeling hypertrophic…

Comparison

cTnI or cTnI mutations complexed into cardiac… vs Wild-type cTnI (cTnI) complexed into cardiac…

Design

Preclinical

Authors

YCYuanhua ChengUniversity of Washington VRVijay S. RaoUniversity of Washington ATAn-Yue TuUniversity of Washington

Discussion

Member takes

Implication

Animal models link these mutations to diastolic impairment in HCM; leaves open whether N-terminal troponin targeting offers therapeutic value.

Structured PICO

Population

Rat ventricular myofibrils and molecular dynamics simulations modeling hypertrophic cardiomyopathy-associated cardiac troponin I (cTnI) mutations R146G and R21C

Intervention

cTnI(R146G) or cTnI(R21C) mutations complexed into cardiac troponin and exchanged into myofibrils, with and without PKA phosphorylation

Comparator

Wild-type cTnI (cTnI(WT)) complexed into cardiac troponin and exchanged into myofibrils

Outcome

Ca(2+) binding affinity to cTn (KCa), affinity of cardiac TnC for cTnI (KC-I), and contraction/relaxation kinetics (Tmax, pCa50, early slow phase relaxation)surrogate

The HCM-associated cTnI mutations R146G and R21C blunt PKA-mediated modulation of cardiac activation and relaxation kinetics, providing a molecular mechanism for their pathophysiological effects.

Cite This Study

Cheng et al. (2015) studied Hypertrophic cardiomyopathy. cTnI(R146G) and cTnI(R21C) mutations vs. cTnI(WT) was evaluated on Contractile activation and relaxation kinetics and response to PKA. Hypertrophic cardiomyopathy-associated mutations cTnI(R146G) and cTnI(R21C) blunted PKA modulation of activation and relaxation kinetics by prohibiting cardiac-specific N-terminal interaction.

synapsesocial.com/papers/6a1c0bf74ebd09f3dfa9600e https://doi.org/10.1074/jbc.m115.683045

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Implication

Animal models link these mutations to diastolic impairment in HCM; leaves open whether N-terminal troponin targeting offers therapeutic value.

Troponin I Mutations R146G and R21C Alter Cardiac Troponin Function, Contractile Properties, and Modulation by Protein Kinase A (PKA)-mediated Phosphorylation

Discussion

Member takes

Implication

Structured PICO

Cite This Study

Troponin I Mutations R146G and R21C Alter Cardiac Troponin Function, Contractile Properties, and Modulation by Protein Kinase A (PKA)-mediated Phosphorylation

Discussion

Member takes

Implication

Structured PICO

Cite This Study

Also Consider

Also Consider