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- W4319936813 abstract "The Frank-Starling Law of the heart is a direct consequence of myofilament length dependent activation (LDA) whereby increased sarcomere length (SL) leads to both increased myocardial Ca2+ sensitivity and maximum force. The molecular mechanisms underlying LDA remain elusive. Since troponin complex binds Ca2+ and regulates myosin-actin interaction during muscle contraction, it has been considered the key element involved LDA. This study aims to explore the molecular mechanism underlying sarcomere LDA and to investigate the functional role of each troponin protein in the LDA regulation. A mutant troponin-I, in which the SP-region was replaced with a G-linker (cTnI-ΔSP), was constructed to study the molecular interaction between troponin-I, troponin-C, and myosin during LDA regulation. The cTnI-ΔSP was used to prevent the functional effect from crossbridge (XB) on the SL-induced Ca2+ sensitivity changes of troponin complex. The SL-induced Ca2+ sensitivity change was monitored by in situ FRET which represents the Ca2+-induced cTnC structural change. Our results show that there are no significant changes of the SL-induced pCa50 shift of troponin in the absence of strong XB, suggesting that besides the XB feedback, the LDA of thin filament may have an alternative pathway involving troponin itself. To further understand the mechanism underlying LDA, recombinant cTnT and cTnI mutants carrying an enzyme cutting site at one end of the IT arm region, respectively, were used in our study. By selectively breaking T1 and T2 of cTnT or separating the C-domain of cTnI from the N-domain, we were able to examine the mechanistic pathway of SL-stretch on the Ca2+-induced structural change of cTnC. Our results provide novel information on the molecular mechanism of how troponin-Ca2+ activation senses myocardial sarcomere stretches to promote myosin-actin interactions at the diastolic level of Ca2+." @default.
- W4319936813 created "2023-02-11" @default.
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- W4319936813 date "2023-02-01" @default.
- W4319936813 modified "2023-09-25" @default.
- W4319936813 title "Mechanistic study of mechanical stretch induced increase in Ca2+ sensitivity of troponin C" @default.
- W4319936813 doi "https://doi.org/10.1016/j.bpj.2022.11.821" @default.
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