Control of in vivo contraction/relaxation kinetics by myosin binding protein C: Protein kinase A phosphorylation-dependent and -independent regulation

Takahiro Nagayama, Eiki Takimoto, Sakthivel Sadayappan, James O. Mudd, J. G. Seidman, Jeffrey Robbins, David A Kass

Research output: Contribution to journalArticle

Abstract

BACKGROUND - Cardiac myosin binding protein-C (cMyBP-C) is a thick-filament protein whose presence and phosphorylation by protein kinase A (PKA) regulates cross-bridge formation and kinetics in isolated myocardium. We tested the influence of cMyBP-C and its PKA-phosphorylation on contraction/relaxation kinetics in intact hearts and revealed its essential role in several classic properties of cardiac function. METHODS AND RESULTS - Comprehensive in situ cardiac pressure-volume analysis was performed in mice harboring a truncation mutation of cMyBP-C (cMyBP-C) that resulted in nondetectable protein versus hearts re-expressing solely wild-type (cMyBP-C) or mutated protein in which known PKA-phosphorylation sites were constitutively suppressed (cMyBP-C). Hearts lacking cMyBP-C had faster early systolic activation, which then terminated prematurely, limiting ejection. Systole remained short at faster heart rates; thus, cMyBP-C hearts displayed minimal rate-dependent decline in diastolic time and cardiac preload. Furthermore, prolongation of pressure relaxation by afterload was markedly blunted in cMyBP-C hearts. All 3 properties were similarly restored to normal in cMyBP-C and cMyBP-C hearts, which supports independence of PKA-phosphorylation. However, the dependence of peak rate of pressure rise on preload was specifically depressed in cMyBP-C hearts, whereas cMyBP-C and cMyBP-C hearts had similar blunted adrenergic and rate-dependent contractile reserve, which supports linkage of these behaviors to PKA-cMyBP-C modification. CONCLUSIONS - cMyBP-C is essential for major properties of cardiac function, including sustaining systole during ejection, the heart-rate dependence of the diastolic time period, and relaxation delay from increased arterial afterload. These are independent of its phosphorylation by PKA, which more specifically modulates early pressure rise rate and adrenergic/heart rate reserve.

Original languageEnglish (US)
Pages (from-to)2399-2408
Number of pages10
JournalCirculation
Volume116
Issue number21
DOIs
StatePublished - Nov 2007

Fingerprint

Cardiac Myosins
Cyclic AMP-Dependent Protein Kinases
Phosphorylation
Pressure
myosin-binding protein C
Systole
Heart Rate
Adrenergic Agents
Cardiac Volume
Proteins

Keywords

  • Diastole
  • Heart
  • Myocardial contraction
  • Sarcomeres

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Control of in vivo contraction/relaxation kinetics by myosin binding protein C : Protein kinase A phosphorylation-dependent and -independent regulation. / Nagayama, Takahiro; Takimoto, Eiki; Sadayappan, Sakthivel; Mudd, James O.; Seidman, J. G.; Robbins, Jeffrey; Kass, David A.

In: Circulation, Vol. 116, No. 21, 11.2007, p. 2399-2408.

Research output: Contribution to journalArticle

Nagayama, Takahiro ; Takimoto, Eiki ; Sadayappan, Sakthivel ; Mudd, James O. ; Seidman, J. G. ; Robbins, Jeffrey ; Kass, David A. / Control of in vivo contraction/relaxation kinetics by myosin binding protein C : Protein kinase A phosphorylation-dependent and -independent regulation. In: Circulation. 2007 ; Vol. 116, No. 21. pp. 2399-2408.
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abstract = "BACKGROUND - Cardiac myosin binding protein-C (cMyBP-C) is a thick-filament protein whose presence and phosphorylation by protein kinase A (PKA) regulates cross-bridge formation and kinetics in isolated myocardium. We tested the influence of cMyBP-C and its PKA-phosphorylation on contraction/relaxation kinetics in intact hearts and revealed its essential role in several classic properties of cardiac function. METHODS AND RESULTS - Comprehensive in situ cardiac pressure-volume analysis was performed in mice harboring a truncation mutation of cMyBP-C (cMyBP-C) that resulted in nondetectable protein versus hearts re-expressing solely wild-type (cMyBP-C) or mutated protein in which known PKA-phosphorylation sites were constitutively suppressed (cMyBP-C). Hearts lacking cMyBP-C had faster early systolic activation, which then terminated prematurely, limiting ejection. Systole remained short at faster heart rates; thus, cMyBP-C hearts displayed minimal rate-dependent decline in diastolic time and cardiac preload. Furthermore, prolongation of pressure relaxation by afterload was markedly blunted in cMyBP-C hearts. All 3 properties were similarly restored to normal in cMyBP-C and cMyBP-C hearts, which supports independence of PKA-phosphorylation. However, the dependence of peak rate of pressure rise on preload was specifically depressed in cMyBP-C hearts, whereas cMyBP-C and cMyBP-C hearts had similar blunted adrenergic and rate-dependent contractile reserve, which supports linkage of these behaviors to PKA-cMyBP-C modification. CONCLUSIONS - cMyBP-C is essential for major properties of cardiac function, including sustaining systole during ejection, the heart-rate dependence of the diastolic time period, and relaxation delay from increased arterial afterload. These are independent of its phosphorylation by PKA, which more specifically modulates early pressure rise rate and adrenergic/heart rate reserve.",
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T1 - Control of in vivo contraction/relaxation kinetics by myosin binding protein C

T2 - Protein kinase A phosphorylation-dependent and -independent regulation

AU - Nagayama, Takahiro

AU - Takimoto, Eiki

AU - Sadayappan, Sakthivel

AU - Mudd, James O.

AU - Seidman, J. G.

AU - Robbins, Jeffrey

AU - Kass, David A

PY - 2007/11

Y1 - 2007/11

N2 - BACKGROUND - Cardiac myosin binding protein-C (cMyBP-C) is a thick-filament protein whose presence and phosphorylation by protein kinase A (PKA) regulates cross-bridge formation and kinetics in isolated myocardium. We tested the influence of cMyBP-C and its PKA-phosphorylation on contraction/relaxation kinetics in intact hearts and revealed its essential role in several classic properties of cardiac function. METHODS AND RESULTS - Comprehensive in situ cardiac pressure-volume analysis was performed in mice harboring a truncation mutation of cMyBP-C (cMyBP-C) that resulted in nondetectable protein versus hearts re-expressing solely wild-type (cMyBP-C) or mutated protein in which known PKA-phosphorylation sites were constitutively suppressed (cMyBP-C). Hearts lacking cMyBP-C had faster early systolic activation, which then terminated prematurely, limiting ejection. Systole remained short at faster heart rates; thus, cMyBP-C hearts displayed minimal rate-dependent decline in diastolic time and cardiac preload. Furthermore, prolongation of pressure relaxation by afterload was markedly blunted in cMyBP-C hearts. All 3 properties were similarly restored to normal in cMyBP-C and cMyBP-C hearts, which supports independence of PKA-phosphorylation. However, the dependence of peak rate of pressure rise on preload was specifically depressed in cMyBP-C hearts, whereas cMyBP-C and cMyBP-C hearts had similar blunted adrenergic and rate-dependent contractile reserve, which supports linkage of these behaviors to PKA-cMyBP-C modification. CONCLUSIONS - cMyBP-C is essential for major properties of cardiac function, including sustaining systole during ejection, the heart-rate dependence of the diastolic time period, and relaxation delay from increased arterial afterload. These are independent of its phosphorylation by PKA, which more specifically modulates early pressure rise rate and adrenergic/heart rate reserve.

AB - BACKGROUND - Cardiac myosin binding protein-C (cMyBP-C) is a thick-filament protein whose presence and phosphorylation by protein kinase A (PKA) regulates cross-bridge formation and kinetics in isolated myocardium. We tested the influence of cMyBP-C and its PKA-phosphorylation on contraction/relaxation kinetics in intact hearts and revealed its essential role in several classic properties of cardiac function. METHODS AND RESULTS - Comprehensive in situ cardiac pressure-volume analysis was performed in mice harboring a truncation mutation of cMyBP-C (cMyBP-C) that resulted in nondetectable protein versus hearts re-expressing solely wild-type (cMyBP-C) or mutated protein in which known PKA-phosphorylation sites were constitutively suppressed (cMyBP-C). Hearts lacking cMyBP-C had faster early systolic activation, which then terminated prematurely, limiting ejection. Systole remained short at faster heart rates; thus, cMyBP-C hearts displayed minimal rate-dependent decline in diastolic time and cardiac preload. Furthermore, prolongation of pressure relaxation by afterload was markedly blunted in cMyBP-C hearts. All 3 properties were similarly restored to normal in cMyBP-C and cMyBP-C hearts, which supports independence of PKA-phosphorylation. However, the dependence of peak rate of pressure rise on preload was specifically depressed in cMyBP-C hearts, whereas cMyBP-C and cMyBP-C hearts had similar blunted adrenergic and rate-dependent contractile reserve, which supports linkage of these behaviors to PKA-cMyBP-C modification. CONCLUSIONS - cMyBP-C is essential for major properties of cardiac function, including sustaining systole during ejection, the heart-rate dependence of the diastolic time period, and relaxation delay from increased arterial afterload. These are independent of its phosphorylation by PKA, which more specifically modulates early pressure rise rate and adrenergic/heart rate reserve.

KW - Diastole

KW - Heart

KW - Myocardial contraction

KW - Sarcomeres

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