Kooiker, Kristina B, Mohran, Saffie, Turner, Kyrah L, Ma, Weikang, Martinson, Amy, Flint, Galina V., Qi, Lin, Gao, Chengqian, Zheng, Yahan, McMillen, Timothy, and others. (2023) Danicamtiv increases myosin recruitment and alters cross-bridge cycling in cardiac muscle. Circulation Research, . ISSN 0009-7330. E-ISSN 1524-4571. (doi:10.1161/circresaha.123.322629) (KAR id:102282)
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| Official URL: https://doi.org/10.1161/circresaha.123.322629 |
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Abstract
Background: Modulating myosin function is a novel therapeutic approach in patients with cardiomyopathy. Danicamtiv is a novel myosin activator with promising preclinical data that is currently in clinical trials. While it is known that danicamtiv increases force and cardiomyocyte contractility without affecting calcium levels, detailed mechanistic studies regarding its mode of action are lacking.
Methods: Permeabilized porcine cardiac tissue and myofibrils were used for X-ray diffraction and mechanical measurements. A mouse model of genetic dilated cardiomyopathy was used to evaluate the ability of danicamtiv to correct the contractile deficient.
Results: Danicamtiv increased force and calcium sensitivity via increasing the number of myosins in the on state and slowing cross-bridge turnover. Our detailed analysis showed that inhibition of ADP release results in decreased cross-bridge turnover with cross bridges staying attached longer and prolonging myofibril relaxation. Danicamtiv corrected decreased calcium sensitivity in demembranated tissue, abnormal twitch magnitude and kinetics in intact cardiac tissue, and reduced ejection fraction in the whole organ.
Conclusions: As demonstrated by the detailed studies of Danicamtiv, increasing myosin recruitment and altering crossbridge cycling are 2 mechanisms to increase force and calcium sensitivity in cardiac muscle. Myosin activators such as Danicamtiv can treat the causative hypocontractile phenotype in genetic dilated cardiomyopathy
| Item Type: | Article |
|---|---|
| DOI/Identification number: | 10.1161/circresaha.123.322629 |
| Uncontrolled keywords: | animal, calcium, cardiomyopathy, myofibril, myosin |
| Subjects: | Q Science |
| Divisions: | Divisions > Division of Natural Sciences > Biosciences |
| Funders: | University of Kent (https://ror.org/00xkeyj56) |
| SWORD Depositor: | JISC Publications Router |
| Depositing User: | JISC Publications Router |
| Date Deposited: | 31 Jul 2023 10:42 UTC |
| Last Modified: | 29 Aug 2023 12:06 UTC |
| Resource URI: | https://kar.kent.ac.uk/id/eprint/102282 (The current URI for this page, for reference purposes) |
University of Kent Author Information
Geeves, Michael A..
| Creator's ORCID: |
 https://orcid.org/0000-0002-9364-8898
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