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Structure and function of cardiac troponin C (TNNC1): Implications for heart failure, cardiomyopathies, and troponin modulating drugs.

ABSTRACT: In striated muscle, the protein troponin complex turns contraction on and off in a calcium-dependent manner. The calcium-sensing component of the complex is troponin C, which is expressed from the TNNC1 gene in both cardiac muscle and slow-twitch skeletal muscle (identical transcript in both tissues) and the TNNC2 gene in fast-twitch skeletal muscle. Cardiac troponin C (cTnC) is made up of two globular EF-hand domains connected by a flexible linker. The structural C-domain (cCTnC) contains two high affinity calcium-binding sites that are always occupied by Ca(2+) or Mg(2+) under physiologic conditions, stabilizing an open conformation that remains anchored to the rest of the troponin complex. In contrast, the regulatory N-domain (cNTnC) contains a single low affinity site that is largely unoccupied at resting calcium concentrations. During muscle activation, calcium binding to cNTnC favors an open conformation that binds to the switch region of troponin I, removing adjacent inhibitory regions of troponin I from actin and allowing muscle contraction to proceed. Regulation of the calcium binding affinity of cNTnC is physiologically important, because it directly impacts the calcium sensitivity of muscle contraction. Calcium sensitivity can be modified by drugs that stabilize the open form of cNTnC, post-translational modifications like phosphorylation of troponin I, or downstream thin filament protein interactions that impact the availability of the troponin I switch region. Recently, mutations in cTnC have been associated with hypertrophic or dilated cardiomyopathy. A detailed understanding of how calcium sensitivity is regulated through the troponin complex is necessary for explaining how mutations perturb its function to promote cardiomyopathy and how post-translational modifications in the thin filament affect heart function and heart failure. Troponin modulating drugs are being developed for the treatment of cardiomyopathies and heart failure.

SUBMITTER: Li MX

PROVIDER: S-EPMC4567495 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature

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Structure and function of cardiac troponin C (TNNC1): Implications for heart failure, cardiomyopathies, and troponin modulating drugs.

Li Monica X MX Hwang Peter M PM

Gene 20150729 2

In striated muscle, the protein troponin complex turns contraction on and off in a calcium-dependent manner. The calcium-sensing component of the complex is troponin C, which is expressed from the TNNC1 gene in both cardiac muscle and slow-twitch skeletal muscle (identical transcript in both tissues) and the TNNC2 gene in fast-twitch skeletal muscle. Cardiac troponin C (cTnC) is made up of two globular EF-hand domains connected by a flexible linker. The structural C-domain (cCTnC) contains two h ...[more]

PMID: 26232335

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Project description:AimsThis study aimed to evaluate the cumulative high-sensitivity cardiac troponin T (hs-cTNT) from admission to 12 months after discharge and its association with mortality after 12 months among patients with acute heart failure (HF).MethodsWe used data from the China Patient-Centered Evaluative Assessment of Cardiac Events Prospective Heart Failure Study (China PEACE 5p-HF Study), which enrolled patients hospitalized primarily for HF from 52 hospitals between 2016 and 2018. We included patients who survived within 12 months and had hs-cTNT data at admission (within 48 h of admission) and 1 and 12 months after discharge. To evaluate the long-term cumulative hs-cTNT, we calculated cumulative hs-cTNT levels and cumulative times of high hs-cTNT level. Patients were divided into groups according to the quartiles of cumulative hs-cTNT levels (Quartiles 1-4) and cumulative times of high hs-cTNT levels (0-3 times). Multivariable Cox models were constructed to examine the association of cumulative hs-cTNT with mortality during the follow-up period.ResultsWe included 1137 patients with a median age of 64 [interquartile range (IQR), 54-73] years; 406 (35.7%) were female. The median cumulative hs-cTNT level was 150 (IQR, 91-241) ng/L*month. Based on the cumulative times of high hs-cTNT levels, 404 (35.5%) patients were with zero time, 203 (17.9%) with one time, 174 (15.3%) with two times, and 356 (31.3%) with three times. During a median follow-up of 4.76 (IQR, 4.25-5.07) years, 303 (26.6%) all-cause deaths occurred. The increasing cumulative hs-cTNT level and cumulative times of high hs-cTNT level were independently associated with excess all-cause mortality. Compared with Quartile 1 group, Quartile 4 had the highest hazard ratio (HR) of all-cause mortality [4.14; 95% confidence interval (CI): 2.51-6.85], followed by Quartile 3 (HR: 3.35; 95% CI: 2.05-5.48) and Quartile 2 (HR: 2.47; 95% CI: 1.49-4.08) groups. Similarly, taking the patients with zero time of high hs-cTNT level as the reference, the HRs were 1.60 (95% CI: 1.05-2.45), 2.61 (95% CI: 1.76-3.87), and 2.86 (95% CI: 1.98-4.14) in patients who had one, two, and three times of high hs-cTNT level, respectively.ConclusionsElevated cumulative hs-cTNT from admission to 12 months after discharge was independently associated with mortality after 12 months among patients with acute HF. Repeated measurements of hs-cTNT after discharge may help monitor the cardiac damage and identify patients with high risk of death.

Dataset Information

Structure and function of cardiac troponin C (TNNC1): Implications for heart failure, cardiomyopathies, and troponin modulating drugs.

Publications

Structure and function of cardiac troponin C (TNNC1): Implications for heart failure, cardiomyopathies, and troponin modulating drugs.

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