What is the clinical evidence from this study?

Population: Cardiac dysfunction. Intervention: Transgenic mutation of cMyBP-C lacking PKA phosphorylation sites (cMyBP-C(t3SA)) vs. Wild-type (WT) and cMyBP-C(tWT) controls. Primary outcome: Crossbridge cycling kinetics (rate constants of relaxation and delayed force development) and echocardiographic function.

What does this research mean for the field?

PKA phosphorylation of cardiac myosin binding protein C (cMyBP-C) accelerates crossbridge kinetics, and the loss of these phosphorylation sites leads to systolic and diastolic dysfunction as well as cardiac hypertrophy. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

What question did this study set out to answer?

To determine whether PKA phosphorylation of cardiac myosin binding protein C (cMyBP-C) modulates crossbridge cycling kinetics and dynamic cardiac contraction.

September 19, 2008Circulation ResearchOpen Access

Acceleration of Crossbridge Kinetics by Protein Kinase A Phosphorylation of Cardiac Myosin Binding Protein C Modulates Cardiac Function

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Key result

Transgenic mice lacking PKA phosphorylation sites on cMyBP-C failed to accelerate crossbridge kinetics in response to PKA treatment, leading to systolic and diastolic dysfunction and hypertrophy.

Key Points

To determine whether PKA phosphorylation of cardiac myosin binding protein C (cMyBP-C) modulates crossbridge cycling kinetics and dynamic cardiac contraction.
Generated transgenic mouse models expressing non-PKA-phosphorylatable mutant cMyBP-C with three Ser-to-Ala mutations [cMyBP-C(t3SA)] or wild-type cMyBP-C [cMyBP-C(tWT)] on a knockout background.
Measured crossbridge cycling kinetics via stretch activation rate constants (k_rel and k_df) in skinned myocardium before and after PKA treatment.
Assessed in vivo basal cardiac structure and dobutamine-induced systolic and diastolic responses using echocardiography.
In cMyBP-C(t3SA) myocardium, baseline k_rel and k_df were preserved but failed to accelerate upon PKA administration, unlike wild-type myocardium.
cMyBP-C(t3SA) hearts exhibited blunted dobutamine-induced systolic augmentation during echocardiographic assessment.
Under basal conditions, cMyBP-C(t3SA) hearts displayed systolic dysfunction, diastolic dysfunction, and hypertrophy, while cMyBP-C(tWT) hearts remained functionally comparable to wild-type.

Structured PICO

Population

Mouse model lacking 3 PKA sites on cMyBP-C (cMyBP-C(t3SA)) developed by transgenic expression of mutant cMyBP-C with Ser-to-Ala mutations on the cMyBP-C knockout background.

Intervention

PKA treatment (in vitro) and dobutamine administration (in vivo)

Comparator

Wild-type (WT) myocardium and cMyBP-C(tWT) controls (transgenic expression of WT cMyBP-C at 72%)

Outcome

Crossbridge cycling kinetics (rate constants of relaxation k(rel) and delayed force development k(df)) and echocardiographic systolic/diastolic functionsurrogate

PKA phosphorylation of cMyBP-C is essential for accelerating crossbridge kinetics, and its absence leads to cardiac dysfunction and hypertrophy.

Discussion

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Implication

Mouse cMyBP-C data implicate PKA phosphorylation in preventing dysfunction; leaves open human therapeutic relevance.

Cite This Study

Tong et al. (2008) studied Cardiac dysfunction. Transgenic mutation of cMyBP-C lacking PKA phosphorylation sites (cMyBP-C(t3SA)) vs. Wild-type (WT) and cMyBP-C(tWT) controls was evaluated on Crossbridge cycling kinetics (rate constants of relaxation and delayed force development) and echocardiographic function. Transgenic mice lacking PKA phosphorylation sites on cMyBP-C failed to accelerate crossbridge kinetics in response to PKA treatment, leading to systolic and diastolic dysfunction and hypertrophy.

synapsesocial.com/papers/6a15cc9f814bf8ec9a4f0ea8 https://doi.org/10.1161/circresaha.108.177683

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Acceleration of Crossbridge Kinetics by Protein Kinase A Phosphorylation of Cardiac Myosin Binding Protein C Modulates Cardiac Function

Key Points

Structured PICO

Discussion

Implication

Cite This Study

Acceleration of Crossbridge Kinetics by Protein Kinase A Phosphorylation of Cardiac Myosin Binding Protein C Modulates Cardiac Function

Key Points

Structured PICO

Discussion

Implication

Cite This Study

Also Consider

Also Consider