What is the clinical evidence from this study?

Study design: Other. Population: Myocardial function. Intervention: PKA treatment vs. Control. Primary outcome: Ca(2+) sensitivity of force (pCa(50)) and activation dependence of the rate of force redevelopment (k(tr)).

What does this research mean for the field?

Protein kinase A (PKA)-induced attenuation of myofilament force response to calcium is driven by the phosphorylation of both cardiac troponin I (cTnI) and cardiac myosin-binding protein C (cMyBP-C), with cMyBP-C phosphorylation specifically reducing calcium sensitivity by accelerating cross-bridge cycling kinetics. Novelty: ClaimNovelty.INCREMENTAL. Consensus alignment: ConsensusAlignment.NEUTRAL.

What question did this study set out to answer?

Determine the distinct functional contributions of cardiac myosin-binding protein C and cardiac troponin I phosphorylation by PKA to myofilament calcium desensitization and cross-bridge kinetics.

November 29, 2010The Journal of General PhysiologyOpen Access

Protein kinase A–induced myofilament desensitization to Ca2+ as a result of phosphorylation of cardiac myosin–binding protein C

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Key result

PKA treatment decreased pCa(50) in WT, cTnI(Ala5), and cMyBP-C(-/-) mouse myocardium by 0.13, 0.08, and 0.09 pCa units, respectively, indicating both cTnI and cMyBP-C phosphorylation attenuate force.

Why the study?

Does PKA treatment alter Ca2+ sensitivity of force and rate of force redevelopment in mouse myocardium with varying phosphorylation states of cTnI and cMyBP-C?

Population

Skinned mouse myocardium expressing: phosphorylatable cTnI and cMyBP-C, phosphorylatable cTnI on a…

Comparison

Cyclic AMP-dependent protein kinase A treatment vs Control (untreated) myocardium

Design

Preclinical

Authors

PCPeter P. ChenMemorial Hermann The Woodlands Hospital JPJitandrakumar R. PatelNorthwestern University IRInna N. RybakovaUniversity of Wisconsin–Madison

Discussion

Member takes

Implication

Supports dual phosphorylation roles in mouse models; hypothesis-generating for human myofilament regulation.

Key Points

Determine the distinct functional contributions of cardiac myosin-binding protein C and cardiac troponin I phosphorylation by PKA to myofilament calcium desensitization and cross-bridge kinetics.
Measured calcium sensitivity of force (pCa50) and rate of force redevelopment (ktr) in skinned mouse myocardium treated with or without PKA.
Evaluated four mouse genotypes: wild type, cardiac troponin I nonphosphorylatable mutant (cTnI(Ala5)), cardiac myosin-binding protein C-null (cMyBP-C(-/-)), and a double-variant strain (cTnI(Ala5)/cMyBP-C(-/-)), supplemented by recombinant cMyBP-C reconstitution.
PKA treatment decreased pCa50 by 0.13 pCa units in wild type, 0.08 units in cTnI(Ala5), and 0.09 units in cMyBP-C(-/-) myocardium, while producing no significant change in cTnI(Ala5)/cMyBP-C(-/-) tissue.
PKA exposure accelerated submaximal ktr in wild type and cTnI(Ala5) myocardium, had no effect in cMyBP-C(-/-) or double-mutant myocardium, and was restored in double mutants following reconstitution with recombinant cMyBP-C.

Structured PICO

Does PKA treatment alter Ca2+ sensitivity of force and rate of force redevelopment in mouse myocardium with varying phosphorylation states of cTnI and cMyBP-C?

Population

Skinned mouse myocardium (isolated in the presence of 2,3-butanedione monoxime) expressing: (a) phosphorylatable cTnI and cMyBP-C (wild type [WT]), (b) phosphorylatable cTnI on a cMyBP-C-null background (cMyBP-C(-/-)), (c) nonphosphorylatable cTnI (cTnI(Ala5)), and (d) nonphosphorylatable cTnI on a cMyBP-C-null background (cTnI(Ala5)/cMyBP-C(-/-))

Intervention

Cyclic AMP-dependent protein kinase A (PKA) treatment

Comparator

Control (untreated) myocardium

Outcome

Ca(2+) sensitivity of force (pCa(50)) and the activation dependence of the rate of force redevelopment (k(tr))surrogate

PKA-induced attenuation in myofilament force response occurs due to phosphorylation of both cTnI and cMyBP-C, with cMyBP-C phosphorylation accelerating cross-bridge cycling kinetics.

Cite This Study

Chen et al. (2010) studied Myocardial function. PKA treatment vs. Control was evaluated on Ca(2+) sensitivity of force (pCa(50)) and activation dependence of the rate of force redevelopment (k(tr)). PKA treatment decreased pCa(50) in WT, cTnI(Ala5), and cMyBP-C(-/-) mouse myocardium by 0.13, 0.08, and 0.09 pCa units, respectively, indicating both cTnI and cMyBP-C phosphorylation attenuate force.

synapsesocial.com/papers/6a0909b814243797f79d0ecc https://doi.org/10.1085/jgp.201010448

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Protein kinase A–induced myofilament desensitization to Ca2+ as a result of phosphorylation of cardiac myosin–binding protein C

Discussion

Member takes

Implication

Key Points

Structured PICO

Cite This Study

Protein kinase A–induced myofilament desensitization to Ca2+ as a result of phosphorylation of cardiac myosin–binding protein C

Discussion

Member takes

Implication

Key Points

Structured PICO

Cite This Study

Also Consider

Also Consider