The contribution of N-terminal truncated cMyBPC to in vivo cardiac function

Autor: Katherine L. Dominic, Joohee Choi, Joshua B. Holmes, Mandeep Singh, Michael J. Majcher, Julian E. Stelzer
Rok vydání: 2023
Předmět:
Zdroj: Journal of General Physiology. 155
ISSN: 1540-7748
0022-1295
DOI: 10.1085/jgp.202213318
Popis: Cardiac myosin binding protein C (cMyBPC) is an 11-domain sarcomeric protein (C0–C10) integral to cardiac muscle regulation. In vitro studies have demonstrated potential functional roles for regions beyond the N-terminus. However, the in vivo contributions of these domains are mostly unknown. Therefore, we examined the in vivo consequences of expression of N-terminal truncated cMyBPC (C3C10). Neonatal cMyBPC−/− mice were injected with AAV9-full length (FL), C3C10 cMyBPC, or saline, and echocardiography was performed 6 wk after injection. We then isolated skinned myocardium from virus-treated hearts and performed mechanical experiments. Our results show that expression of C3C10 cMyBPC in cMyBPC−/− mice resulted in a 28% increase in systolic ejection fraction compared to saline-injected cMyBPC−/− mice and a 25% decrease in left ventricle mass-to-body weight ratio. However, unlike expression of FL cMyBPC, there was no prolongation of ejection time compared to saline-injected mice. In vitro mechanical experiments demonstrated that functional improvements in cMyBPC−/− mice expressing C3C10 were primarily due to a 35% reduction in the rate of cross-bridge recruitment at submaximal Ca2+ concentrations when compared to hearts from saline-injected cMyBPC−/− mice. However, unlike the expression of FL cMyBPC, there was no change in the rate of cross-bridge detachment when compared to saline-injected mice. Our data demonstrate that regions of cMyBPC beyond the N-terminus are important for in vivo cardiac function, and have divergent effects on cross-bridge behavior. Elucidating the molecular mechanisms of cMyBPC region-specific function could allow for development of targeted approaches to manipulate specific aspects of cardiac contractile function.
Databáze: OpenAIRE
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