Biochemical characterisation of Troponin C mutations causing hypertrophic and dilated cardiomyopathies

Kalyva, Athanasia; Parthenakis, Fragiskos I.; Marketou, Maria; Kontaraki, Joanna; Vardas, Panos

doi:10.1007/s10974-014-9382-0

Cited by 28 publications

(24 citation statements)

References 66 publications

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“…While TNNC1 human mutations are rare in humans, they have been attributed to causing HCM or DCM (Kalyva et al, 2014). We also used mutant cTnCs because they represent the proximal Ca 2+ binding element of the sarcomere, hence allowing for a more direct modulation of the Ca 2+ -tension relationship without potential confounding effects.…”

Section: Discussionmentioning

confidence: 99%

A Tension-Based Model Distinguishes Hypertrophic versus Dilated Cardiomyopathy

Davis

Davis²,

Correll

et al. 2016

Cell

209

216

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SUMMARY The heart either hypertrophies or dilates in response to familial mutations in genes encoding sarcomeric proteins, which are responsible for contraction and pumping. These mutations typically alter calcium-dependent tension generation within the sarcomeres, but how this translates into the spectrum of hypertrophic versus dilated cardiomyopathy is unknown. By generating a series of cardiac-specific mouse models that permit the systematic tuning of sarcomeric tension generation and calcium fluxing, we identify a significant relationship between the magnitude of tension developed over time and heart growth. When formulated into a computational model the integral of myofilament tension development predicts hypertrophic and dilated cardiomyopathies in mice associated with essentially any sarcomeric gene mutations, but also accurately predicts human cardiac phenotypes from data generated in induced-pluripotent stem cell-derived myocytes from familial cardiomyopathy patients. This tension-based model also has the potential to inform pharmacologic treatment options in cardiomyopathy patients.

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Section: Discussionmentioning

confidence: 99%

A Tension-Based Model Distinguishes Hypertrophic versus Dilated Cardiomyopathy

Davis

Davis²,

Correll

et al. 2016

Cell

209

216

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“…To date, 7 mutations associated with HCM (A8V, L29Q, A31S, C84Y, Q122AfsX30, E134D, D145E) and 7 mutations associated with dilated cardiomyopathy (DCM) (Y5H, Q50R, E59D/D75Y, M103I, D145E, I148V, G159D) in cTnC have been reported. A recent review 101 has summarized the biochemical characterization of these mutations, but we will briefly survey them here.…”

Section: Hypertrophic Cardiomyopathy-associated Mutationsmentioning

confidence: 99%

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

Hwang

2015

Gene

106

105

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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 Ca2+ or Mg2+ 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.

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“…One troponin complex binds to every seventh actin monomer. The complex has three regulatory proteins: troponin C, troponin C, and troponin T. Troponin C (TnC) binds to a calcium molecule [7]. Troponin I (TnI) is the inhibitory subunit while troponin T (TnT) binds to Tm [8,9].…”

Section: Introductionmentioning

confidence: 99%

Effect of starvation on expression of troponin complex genes and ER stress associated genes in skeletal muscles

Kwon¹,

Yoo²,

Ko³

et al. 2018

biomedicalresearch

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Little is known about the mechanism of gene expression changes in skeletal muscle during starvation. This study investigated the influence of starvation on gene expression of troponin complex (TnC, TnI and TnT), tropomyosin (Tpm), and endoplasmic reticulum (ER) stress associated proteins (BiP, calreticulin, PDI, and ATF6) in three kinds of skeletal muscles of Gryllus bimaculatus. Dorsal ventral flight muscle (DVM), dorsal longitudinal, and dorsal wing flight muscles (DWM) were identified as typical skeletal muscles by H&E staining. Obvious gene expression was detected in the DVM, but not in the DLM or DWM. In addition to gene expression in DVM, gene expression of decorin, a type of myokine, was also significantly increased by starvation. This is the first study that reports the effect of starvation on expression of troponin complex genes and ER stress associated genes in three types of skeletal muscles.

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Biochemical characterisation of Troponin C mutations causing hypertrophic and dilated cardiomyopathies

Cited by 28 publications

References 66 publications

A Tension-Based Model Distinguishes Hypertrophic versus Dilated Cardiomyopathy

A Tension-Based Model Distinguishes Hypertrophic versus Dilated Cardiomyopathy

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

Effect of starvation on expression of troponin complex genes and ER stress associated genes in skeletal muscles

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