Point mutations in the tri-helix bundle of the M-domain of cardiac myosin binding protein-C influence systolic duration and delay cardiac relaxation. (June 2018)

• Record Type: Journal Article
• Authors: van Dijk, Sabine J.; Kooiker, Kristina B.; Napierski, Nathaniel C.; Touma, Katia D.; Mazzalupo, Stacy; Harris, Samantha P.
• Is Part Of: Journal of molecular and cellular cardiology. Volume 119(2018)
• Page Start: 116
• Page End: 124
• Publication Date: 2018-06
• Subjects: Heart -- Cardiac myosin binding protein C -- Actin -- Transgenic mice -- Cardiac function; Cardiology -- Periodicals; Heart Diseases -- Periodicals; Molecular Biology -- Periodicals; Cardiologie -- Périodiques; Cardiology; Electronic journals; Periodicals; 616.12
• DOI: 10.1016/j.yjmcc.2018.05.001
• Languages: English
• ISSNs: 0022-2828

Abstract

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. Highlights: Cardiac myosin binding protein C binding to actin affects cardiac function in vivo. cMyBP-C regulates timing of systole through binding to actin. Increased binding of cMyBP-C to actin slowed cardiac relaxation. Increased cMyBP-C binding to actin caused diastolic dysfunction in mice.