cMyBPC phosphorylation modulates the effect of omecamtiv mecarbil on myocardial force generation

Autor: Joshua B Holmes, Nikhil Madugula, Ranganath Mamidi, Katherine L Dominic, Chang Yoon Doh, Julian E. Stelzer
Rok vydání: 2021
Předmět:
Zdroj: The Journal of General Physiology
ISSN: 1540-7748
0022-1295
DOI: 10.1085/jgp.202012816
Popis: Mamidi et al. investigate the effect of cardiac myosin-binding protein C (cMyBPC) phosphorylation on the response to omecamtiv mecarbil (OM), a candidate heart failure therapy. They show that OM uncouples myocardial force dynamics from cMyBPC phosphorylation, suggesting important therapeutic constraints.
Omecamtiv mecarbil (OM), a direct myosin motor activator, is currently being tested as a therapeutic replacement for conventional inotropes in heart failure (HF) patients. It is known that HF patients exhibit dysregulated β-adrenergic signaling and decreased cardiac myosin-binding protein C (cMyBPC) phosphorylation, a critical modulator of myocardial force generation. However, the functional effects of OM in conditions of altered cMyBPC phosphorylation have not been established. Here, we tested the effects of OM on force generation and cross-bridge (XB) kinetics using murine myocardial preparations isolated from wild-type (WT) hearts and from hearts expressing S273A, S282A, and S302A substitutions (SA) in the M domain, between the C1 and C2 domains of cMyBPC, which cannot be phosphorylated. At submaximal Ca2+ activations, OM-mediated force enhancements were less pronounced in SA than in WT myocardial preparations. Additionally, SA myocardial preparations lacked the dose-dependent increases in force that were observed in WT myocardial preparations. Following OM incubation, the basal differences in the rate of XB detachment (krel) between WT and SA myocardial preparations were abolished, suggesting that OM differentially affects the XB behavior when cMyBPC phosphorylation is reduced. Similarly, in myocardial preparations pretreated with protein kinase A to phosphorylate cMyBPC, incubation with OM significantly slowed krel in both the WT and SA myocardial preparations. Collectively, our data suggest there is a strong interplay between the effects of OM and XB behavior, such that it effectively uncouples the sarcomere from cMyBPC phosphorylation levels. Our findings imply that OM may significantly alter the in vivo cardiac response to β-adrenergic stimulation.
Databáze: OpenAIRE
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