Myocardial infarction-induced N-terminal fragment of cardiac myosin-binding protein C (cMyBP-C) impairs myofilament function in human myocardium

Namthip Witayavanitkul, Younss Ait Mou, Diederik W D Kuster, Ramzi J. Khairallah, Jason Sarkey, Suresh Govindan, Xin Chen, Ying Ge, Sudarsan Rajan, David F. Wieczorek, Thomas Irving, Margaret V. Westfall, Pieter P. De Tombe, Sakthivel Sadayappan

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

Myocardial infarction (MI) is associated with depressed cardiac contractile function and progression to heart failure. Cardiac myosin-binding protein C, a cardiac-specific myofilament protein, is proteolyzed post-MI in humans, which results in an N-terminal fragment, C0-C1f. The presence of C0-C1f in cultured cardiomyocytes results in decreased Ca2+ transients and cell shortening, abnormalities sufficient for the induction of heart failure in a mouse model. However, the underlying mechanisms remain unclear. Here, we investigate the association between C0-C1f and altered contractility in human cardiac myofilaments in vitro. To accomplish this, we generated recombinant human C0-C1f (hC0C1f) and incorporated it into permeabilized human left ventricular myocardium. Mechanical properties were studied at short (2 μm) and long (2.3 μm) sarcomere length (SL). Our data demonstrate that the presence of hC0C1f in the sarcomere had the greatest effect at short, but not long, SL, decreasing maximal force and myofilament Ca2+ sensitivity. Moreover, hC0C1f led to increased cooperative activation, cross-bridge cycling kinetics, and tension cost, with greater effects at short SL. We further established that the effects of hC0C1f occur through direct interaction with actin and α-tropomyosin. Our data demonstrate that the presence of hC0C1f in the sarcomere is sufficient to induce depressed myofilament function and Ca2+ sensitivity in otherwise healthy human donor myocardium. Decreased cardiac function post-MI may result, in part, from the ability of hC0C1f to bind actin and α-tropomyosin, suggesting that cleaved C0-C1f could act as a poison polypeptide and disrupt the interaction of native cardiac myosinbinding protein C with the thin filament.

Original languageEnglish
Pages (from-to)8818-8827
Number of pages10
JournalJournal of Biological Chemistry
Volume289
Issue number13
DOIs
Publication statusPublished - 30 Mar 2014
Externally publishedYes

Fingerprint

Cardiac Myosins
Myofibrils
Myocardium
Tropomyosin
Myocardial Infarction
Sarcomeres
Actins
Poisons
Protein C
Chemical activation
Association reactions
Mechanical properties
Peptides
Kinetics
Heart Failure
myosin-binding protein C
Costs
Proteins
Cardiac Myocytes

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Witayavanitkul, N., Mou, Y. A., Kuster, D. W. D., Khairallah, R. J., Sarkey, J., Govindan, S., ... Sadayappan, S. (2014). Myocardial infarction-induced N-terminal fragment of cardiac myosin-binding protein C (cMyBP-C) impairs myofilament function in human myocardium. Journal of Biological Chemistry, 289(13), 8818-8827. https://doi.org/10.1074/jbc.M113.541128

Myocardial infarction-induced N-terminal fragment of cardiac myosin-binding protein C (cMyBP-C) impairs myofilament function in human myocardium. / Witayavanitkul, Namthip; Mou, Younss Ait; Kuster, Diederik W D; Khairallah, Ramzi J.; Sarkey, Jason; Govindan, Suresh; Chen, Xin; Ge, Ying; Rajan, Sudarsan; Wieczorek, David F.; Irving, Thomas; Westfall, Margaret V.; De Tombe, Pieter P.; Sadayappan, Sakthivel.

In: Journal of Biological Chemistry, Vol. 289, No. 13, 30.03.2014, p. 8818-8827.

Research output: Contribution to journalArticle

Witayavanitkul, N, Mou, YA, Kuster, DWD, Khairallah, RJ, Sarkey, J, Govindan, S, Chen, X, Ge, Y, Rajan, S, Wieczorek, DF, Irving, T, Westfall, MV, De Tombe, PP & Sadayappan, S 2014, 'Myocardial infarction-induced N-terminal fragment of cardiac myosin-binding protein C (cMyBP-C) impairs myofilament function in human myocardium', Journal of Biological Chemistry, vol. 289, no. 13, pp. 8818-8827. https://doi.org/10.1074/jbc.M113.541128
Witayavanitkul, Namthip ; Mou, Younss Ait ; Kuster, Diederik W D ; Khairallah, Ramzi J. ; Sarkey, Jason ; Govindan, Suresh ; Chen, Xin ; Ge, Ying ; Rajan, Sudarsan ; Wieczorek, David F. ; Irving, Thomas ; Westfall, Margaret V. ; De Tombe, Pieter P. ; Sadayappan, Sakthivel. / Myocardial infarction-induced N-terminal fragment of cardiac myosin-binding protein C (cMyBP-C) impairs myofilament function in human myocardium. In: Journal of Biological Chemistry. 2014 ; Vol. 289, No. 13. pp. 8818-8827.
@article{f19c1dfcc2a24bd2be6a2c99dc8a402d,
title = "Myocardial infarction-induced N-terminal fragment of cardiac myosin-binding protein C (cMyBP-C) impairs myofilament function in human myocardium",
abstract = "Myocardial infarction (MI) is associated with depressed cardiac contractile function and progression to heart failure. Cardiac myosin-binding protein C, a cardiac-specific myofilament protein, is proteolyzed post-MI in humans, which results in an N-terminal fragment, C0-C1f. The presence of C0-C1f in cultured cardiomyocytes results in decreased Ca2+ transients and cell shortening, abnormalities sufficient for the induction of heart failure in a mouse model. However, the underlying mechanisms remain unclear. Here, we investigate the association between C0-C1f and altered contractility in human cardiac myofilaments in vitro. To accomplish this, we generated recombinant human C0-C1f (hC0C1f) and incorporated it into permeabilized human left ventricular myocardium. Mechanical properties were studied at short (2 μm) and long (2.3 μm) sarcomere length (SL). Our data demonstrate that the presence of hC0C1f in the sarcomere had the greatest effect at short, but not long, SL, decreasing maximal force and myofilament Ca2+ sensitivity. Moreover, hC0C1f led to increased cooperative activation, cross-bridge cycling kinetics, and tension cost, with greater effects at short SL. We further established that the effects of hC0C1f occur through direct interaction with actin and α-tropomyosin. Our data demonstrate that the presence of hC0C1f in the sarcomere is sufficient to induce depressed myofilament function and Ca2+ sensitivity in otherwise healthy human donor myocardium. Decreased cardiac function post-MI may result, in part, from the ability of hC0C1f to bind actin and α-tropomyosin, suggesting that cleaved C0-C1f could act as a poison polypeptide and disrupt the interaction of native cardiac myosinbinding protein C with the thin filament.",
author = "Namthip Witayavanitkul and Mou, {Younss Ait} and Kuster, {Diederik W D} and Khairallah, {Ramzi J.} and Jason Sarkey and Suresh Govindan and Xin Chen and Ying Ge and Sudarsan Rajan and Wieczorek, {David F.} and Thomas Irving and Westfall, {Margaret V.} and {De Tombe}, {Pieter P.} and Sakthivel Sadayappan",
year = "2014",
month = "3",
day = "30",
doi = "10.1074/jbc.M113.541128",
language = "English",
volume = "289",
pages = "8818--8827",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "13",

}

TY - JOUR

T1 - Myocardial infarction-induced N-terminal fragment of cardiac myosin-binding protein C (cMyBP-C) impairs myofilament function in human myocardium

AU - Witayavanitkul, Namthip

AU - Mou, Younss Ait

AU - Kuster, Diederik W D

AU - Khairallah, Ramzi J.

AU - Sarkey, Jason

AU - Govindan, Suresh

AU - Chen, Xin

AU - Ge, Ying

AU - Rajan, Sudarsan

AU - Wieczorek, David F.

AU - Irving, Thomas

AU - Westfall, Margaret V.

AU - De Tombe, Pieter P.

AU - Sadayappan, Sakthivel

PY - 2014/3/30

Y1 - 2014/3/30

N2 - Myocardial infarction (MI) is associated with depressed cardiac contractile function and progression to heart failure. Cardiac myosin-binding protein C, a cardiac-specific myofilament protein, is proteolyzed post-MI in humans, which results in an N-terminal fragment, C0-C1f. The presence of C0-C1f in cultured cardiomyocytes results in decreased Ca2+ transients and cell shortening, abnormalities sufficient for the induction of heart failure in a mouse model. However, the underlying mechanisms remain unclear. Here, we investigate the association between C0-C1f and altered contractility in human cardiac myofilaments in vitro. To accomplish this, we generated recombinant human C0-C1f (hC0C1f) and incorporated it into permeabilized human left ventricular myocardium. Mechanical properties were studied at short (2 μm) and long (2.3 μm) sarcomere length (SL). Our data demonstrate that the presence of hC0C1f in the sarcomere had the greatest effect at short, but not long, SL, decreasing maximal force and myofilament Ca2+ sensitivity. Moreover, hC0C1f led to increased cooperative activation, cross-bridge cycling kinetics, and tension cost, with greater effects at short SL. We further established that the effects of hC0C1f occur through direct interaction with actin and α-tropomyosin. Our data demonstrate that the presence of hC0C1f in the sarcomere is sufficient to induce depressed myofilament function and Ca2+ sensitivity in otherwise healthy human donor myocardium. Decreased cardiac function post-MI may result, in part, from the ability of hC0C1f to bind actin and α-tropomyosin, suggesting that cleaved C0-C1f could act as a poison polypeptide and disrupt the interaction of native cardiac myosinbinding protein C with the thin filament.

AB - Myocardial infarction (MI) is associated with depressed cardiac contractile function and progression to heart failure. Cardiac myosin-binding protein C, a cardiac-specific myofilament protein, is proteolyzed post-MI in humans, which results in an N-terminal fragment, C0-C1f. The presence of C0-C1f in cultured cardiomyocytes results in decreased Ca2+ transients and cell shortening, abnormalities sufficient for the induction of heart failure in a mouse model. However, the underlying mechanisms remain unclear. Here, we investigate the association between C0-C1f and altered contractility in human cardiac myofilaments in vitro. To accomplish this, we generated recombinant human C0-C1f (hC0C1f) and incorporated it into permeabilized human left ventricular myocardium. Mechanical properties were studied at short (2 μm) and long (2.3 μm) sarcomere length (SL). Our data demonstrate that the presence of hC0C1f in the sarcomere had the greatest effect at short, but not long, SL, decreasing maximal force and myofilament Ca2+ sensitivity. Moreover, hC0C1f led to increased cooperative activation, cross-bridge cycling kinetics, and tension cost, with greater effects at short SL. We further established that the effects of hC0C1f occur through direct interaction with actin and α-tropomyosin. Our data demonstrate that the presence of hC0C1f in the sarcomere is sufficient to induce depressed myofilament function and Ca2+ sensitivity in otherwise healthy human donor myocardium. Decreased cardiac function post-MI may result, in part, from the ability of hC0C1f to bind actin and α-tropomyosin, suggesting that cleaved C0-C1f could act as a poison polypeptide and disrupt the interaction of native cardiac myosinbinding protein C with the thin filament.

UR - http://www.scopus.com/inward/record.url?scp=84897406351&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84897406351&partnerID=8YFLogxK

U2 - 10.1074/jbc.M113.541128

DO - 10.1074/jbc.M113.541128

M3 - Article

C2 - 24509847

AN - SCOPUS:84897406351

VL - 289

SP - 8818

EP - 8827

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 13

ER -