Point mutations in the tri-helix bundle of the M-domain of cardiac myosin binding protein-C influence systolic duration and delay cardiac relaxation

Sabine J. van Dijk, Kristina B. Kooiker, Nathaniel C. Napierski, Katia D. Touma, Stacy Mazzalupo, Samantha - Harris

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Cardiac myosin binding protein-C (cMyBP-C) is an essential regulatory protein required for proper systolic contraction and diastolic relaxation. We previously showed that N′-terminal domains of cMyBP-C stimulate contraction by binding to actin and activating the thin filament in vitro. In principle, thin filament activating effects of cMyBP-C could influence contraction and relaxation rates, or augment force amplitude in vivo. cMyBP-C binding to actin could also contribute to an internal load that slows muscle shortening velocity as previously hypothesized. However, the functional significance of cMyBP-C binding to actin has not yet been established in vivo. We previously identified an actin binding site in the regulatory M-domain of cMyBP-C and described two missense mutations that either increased (L348P) or decreased (E330K) binding affinity of recombinant cMyBP-C N′-terminal domains for actin in vitro. Here we created transgenic mice with either the L348P or E330K mutations to determine the functional significance of cMyBP-C binding to actin in vivo. Results showed that enhanced binding of cMyBP-C to actin in L348P-Tg mice prolonged the time to end-systole and slowed relaxation rates. Reduced interactions between cMyBP-C and actin in E330K-Tg mice had the opposite effect and significantly shortened the duration of ejection. Neither mouse model displayed overt systolic dysfunction, but L348P-Tg mice showed diastolic dysfunction presumably resulting from delayed relaxation. We conclude that cMyBP-C binding to actin contributes to sustained thin filament activation at the end of systole and during isovolumetric relaxation. These results provide the first functional evidence that cMyBP-C interactions with actin influence cardiac function in vivo.

Original languageEnglish (US)
Pages (from-to)116-124
Number of pages9
JournalJournal of Molecular and Cellular Cardiology
Volume119
DOIs
StatePublished - Jun 1 2018

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Cardiac Myosins
Point Mutation
Actins
Protein Binding
Systole
myosin-binding protein C
Missense Mutation
Transgenic Mice

Keywords

  • Actin
  • Cardiac function
  • Cardiac myosin binding protein C
  • Heart
  • Transgenic mice

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

Cite this

Point mutations in the tri-helix bundle of the M-domain of cardiac myosin binding protein-C influence systolic duration and delay cardiac relaxation. / van Dijk, Sabine J.; Kooiker, Kristina B.; Napierski, Nathaniel C.; Touma, Katia D.; Mazzalupo, Stacy; Harris, Samantha -.

In: Journal of Molecular and Cellular Cardiology, Vol. 119, 01.06.2018, p. 116-124.

Research output: Contribution to journalArticle

van Dijk, Sabine J. ; Kooiker, Kristina B. ; Napierski, Nathaniel C. ; Touma, Katia D. ; Mazzalupo, Stacy ; Harris, Samantha -. / Point mutations in the tri-helix bundle of the M-domain of cardiac myosin binding protein-C influence systolic duration and delay cardiac relaxation. In: Journal of Molecular and Cellular Cardiology. 2018 ; Vol. 119. pp. 116-124.
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AU - Touma, Katia D.

AU - Mazzalupo, Stacy

AU - Harris, Samantha -

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