Troponin structure and function: a view of recent progress

Marston, Steven B.; Zamora, Juan Eiros

doi:10.1007/s10974-019-09513-1

Cited by 67 publications

(77 citation statements)

References 79 publications

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“…Our simulated twitches suggest that the TI of D230N cardiomyocytes can be greatly increased by augmenting Ca 2+ binding to cTnC ( Figure 2B ). When Ca 2+ binds to cTnC, allosteric interactions in the Tn complex cause the inhibitory peptide region of cTnI to reduce its interaction with actin ( 23 – 25 ), which enables Tm to move from a blocked state to closed and open states that permit varying degrees of XB binding ( 22 ). The activated state of the Tn-Tm complex is stabilized by interactions between the switch peptide of cTnI and cTnC (see ref.…”

Section: Resultsmentioning

confidence: 99%

Modulating the tension-time integral of the cardiac twitch prevents dilated cardiomyopathy in murine hearts

Powers

Kooiker

Mason³

et al. 2020

JCI Insight

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Dilated cardiomyopathy (DCM) is often associated with sarcomere protein mutations that confer reduced myofilament tension–generating capacity. We demonstrated that cardiac twitch tension-time integrals can be targeted and tuned to prevent DCM remodeling in hearts with contractile dysfunction. We employed a transgenic murine model of DCM caused by the D230N-tropomyosin (Tm) mutation and designed a sarcomere-based intervention specifically targeting the twitch tension-time integral of D230N-Tm hearts using multiscale computational models of intramolecular and intermolecular interactions in the thin filament and cell-level contractile simulations. Our models predicted that increasing the calcium sensitivity of thin filament activation using the cardiac troponin C (cTnC) variant L48Q can sufficiently augment twitch tension-time integrals of D230N-Tm hearts. Indeed, cardiac muscle isolated from double-transgenic hearts expressing D230N-Tm and L48Q cTnC had increased calcium sensitivity of tension development and increased twitch tension-time integrals compared with preparations from hearts with D230N-Tm alone. Longitudinal echocardiographic measurements revealed that DTG hearts retained normal cardiac morphology and function, whereas D230N-Tm hearts developed progressive DCM. We present a computational and experimental framework for targeting molecular mechanisms governing the twitch tension of cardiomyopathic hearts to counteract putative mechanical drivers of adverse remodeling and open possibilities for tension-based treatments of genetic cardiomyopathies.

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Section: Resultsmentioning

confidence: 99%

Modulating the tension-time integral of the cardiac twitch prevents dilated cardiomyopathy in murine hearts

Powers

Kooiker

Mason³

et al. 2020

JCI Insight

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“…HCM and DCM mutations can occur in the same protein like in human cardiac troponin T (hcTnT) (Kamisago et al, 2000;Marston and Hodgkinson, 2001;Song et al, 2005;Lu et al, 2013). Cardiac troponin T (cTnT) transfers the Ca 2+ binding event from cardiac troponin C (cTnC) to troponin I (cTnI) and tropomyosin (Tm) [recently reviewed in (Marston and Zamora, 2020)]. Previous studies investigating individual mutations in these regulatory proteins associated with HCM and DCM either mostly reported negative or no consequence of mutations on LDA (Li et al, 2013;Sequeira et al, 2013;Mickelson and Chandra, 2017;Chandra, 2018, 2019).…”

Section: Introductionmentioning

confidence: 99%

Hypertrophic and Dilated Cardiomyopathy-Associated Troponin T Mutations R130C and ΔK210 Oppositely Affect Length-Dependent Calcium Sensitivity of Force Generation

et al. 2020

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Length-dependent activation of calcium-dependent myocardial force generation provides the basis for the Frank-Starling mechanism. To directly compare the effects of mutations associated with hypertrophic cardiomyopathy and dilated cardiomyopathy, the native troponin complex in skinned trabecular fibers of guinea pigs was exchanged with recombinant heterotrimeric, human, cardiac troponin complexes containing different human cardiac troponin T subunits (hcTnT): hypertrophic cardiomyopathyassociated hcTnT R130C , dilated cardiomyopathy-associated hcTnT K210 or the wild type hcTnT (hcTnT WT) serving as control. Force-calcium relations of exchanged fibers were explored at short fiber length defined as 110% of slack length (L 0) and long fiber length defined as 125% of L 0 (1.25 L 0). At short fiber length (1.1 L 0), calcium sensitivity of force generation expressed by −log [Ca 2+ ] required for half-maximum force generation (pCa 50) was highest for the hypertrophic cardiomyopathy-associated mutation R130C (5.657 ± 0.019), intermediate for the wild type control (5.580 ± 0.028) and lowest for the dilated cardiomyopathy-associated mutation K210 (5.325 ± 0.038). Lengthening fibers from 1.1 L 0 to 1.25 L 0 increased calcium sensitivity in fibers containing hcTnT R130C (delta-pCa 50 = +0.030 ± 0.010), did not alter calcium sensitivity in the wild type control (delta-pCa 50 = −0.001 ± 0.010), and decreased calcium sensitivity in fibers containing hcTnT K210 (delta-pCa 50 = −0.034 ± 0.013). Length-dependent activation indicated by the delta-pCa 50 was highly significantly (P < 0.001) different between the two mutations. We hypothesize that primary effects of mutations on length-dependent activation contribute to the development of the diverging phenotypes in hypertrophic and dilated cardiomyopathy.

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“…We highlight the upstream effect that TNNI3 may be having on heart muscle contraction, which may be having a negative downstream effect on a wide range of biological processes in the nervous, respiratory and digestive systems (see Supplementary Figure 1 for a bubble plot of genetically associated processes with TNNI3). In addition, we identify levosimendan, a positive inotropic agent having ATP-dependent potassium-channel-opening and calcium-sensitizing effects by binding to a calcium sensing myocardial complex consisting of cardiac troponin C and troponin I(20) ,(21,22) . This is a clinically approved drug used for heart failure, kidney failure and SARS (https://www.targetvalidation.org/summary?drug=CHEMBL2051955).…”

Section: Resultsmentioning

confidence: 99%

Proteome-wide Mendelian randomization identifies causal links between blood proteins and severe COVID-19

Palmos

Millischer

Menon

et al. 2021

Preprint

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The COVID-19 pandemic death toll now surpasses two million individuals and there is a need for early identification of individuals at increased risk of mortality. Host genetic variation partially drives the immune and biochemical responses to COVID-19 that lead to risk of mortality. We identify and prioritise blood proteins and biomarkers that may indicate increased risk for severe COVID-19, via a proteome Mendelian randomization approach by collecting genome-wide association study (GWAS) summary statistics for >4,000 blood proteins. After multiple testing correction, troponin I3, cardiac type (TNNI3) had the strongest effect (odds ratio (O.R.) of 6.86 per standard deviation increase in protein level), with proteinase 3 (PRTN3) (O.R.=2.48), major histocompatibility complex, class II, DQ alpha 2 (HLA-DQA2) (O.R.=2.29), the C4A-C4B heterodimer (O.R.=1.76) and low-density lipoprotein receptor-related protein associated protein 1 (LRPAP1) (O.R.=1.73) also being associated with higher odds of severe COVID-19. Conversely, major histocompatibility complex class I polypeptide-related sequence A (MHC1A) (O.R.=0.6) and natural cytotoxicity triggering receptor 3 (NCR3) (O.R.=0.46) were associated with lower odds. These proteins are involved in heart muscle contraction, natural killer and antigen presenting cells, and the major histocompatibility complex. Based on these findings, it may be possible to better predict which patients may develop severe COVID-19 and to design better treatments targeting the implicated mechanisms.

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Troponin structure and function: a view of recent progress

Cited by 67 publications

References 79 publications

Modulating the tension-time integral of the cardiac twitch prevents dilated cardiomyopathy in murine hearts

Modulating the tension-time integral of the cardiac twitch prevents dilated cardiomyopathy in murine hearts

Hypertrophic and Dilated Cardiomyopathy-Associated Troponin T Mutations R130C and ΔK210 Oppositely Affect Length-Dependent Calcium Sensitivity of Force Generation

Proteome-wide Mendelian randomization identifies causal links between blood proteins and severe COVID-19

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