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• W2019001590 abstract "Previously, we reported the generation and characterization of an R21C cardiac troponin I (cTnI) knock-in (KI) mouse model linked to hypertrophic cardiomyopathy in humans (Biophys J Vol 98, Issue 3, Suppl 1, 148a). The R21C+/+ (homozygote) mice displayed decreased cTnI phosphorylation at serines23/24, decreased Ca2+ sensitivity response (rightward shift) of the myofilament upon PKA incubation and marked late stage heart hypertrophy (≥ 12 months of age). Here, we further investigated effects of the cTnI R21C mutation on intracellular Ca2+ ([Ca2+]i) and contractility in R21C+/+ cardiomyocytes before and after 100 nmol/L isoproterenol (ISO) treatment. Incubation with ISO slightly reduced diastolic [Ca2+]i in R21C+/+ cardiomyocytes, consistent with increased resting sarcomere length (SL) (relaxation), however diastolic [Ca2+]i increased in WT cardiomyocytes without altering resting SL. Despite similar SL shortening between both strains at baseline or after ISO, WT had a strong response to ISO with increased ΔCa2+ amplitude (systolic [Ca2+]i - diastolic [Ca2+]i) but no significant increase in R21C+/+ throughout a range of frequencies was observed. Ca2+ decay was similar between strains before or after ISO, however SL relaxation in R21C+/+ was slower but with stronger response to ISO compared to WT. Furthermore, the rate of relaxation of R21C+/+ skinned fibers was measured by flashphotolysis prior to and after PKA incubation. Data was fit with a double exponential and major changes were identified in the first rate constant (k1). After PKA incubation, k1 in WT skinned fibers significantly increased (19.02/sec to 28.49/sec). In comparison, k1 in R21C+/+ skinned fibers increased from (22.66/sec to 26.40/sec) before and after PKA treatment. These data taken together demonstrates that the HCM R21C-cTnI mutation increases intracellular calcium buffering and delays sarcomere relaxation without changing Ca2+ decay. Supported by NIH R01-HL432325 (JDP)." @default.
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• W2019001590 date "2012-01-01" @default.
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• W2019001590 title "The Hypertrophic Cardiomyopathy Mutation R21C in Cardiac Troponin I Affects Ca2+ Homeostasis and Contractility in Transgenic Cardiomyocytes" @default.
• W2019001590 doi "https://doi.org/10.1016/j.bpj.2011.11.857" @default.
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