Hypertrophic Cardiomyopathy Cardiac Troponin C Mutations Differentially Affect Slow Skeletal and Cardiac Muscle Regulation

Veltri, Tiago; Landim-Vieira, Maicon; Parvatiyar, Michelle S.; Gonzalez-Martinez, David; Jones, Karissa M. Dieseldorff; Michell, Clara A.; Dweck, David; Landstrom, Andrew P.; Chase, P. Bryant; Pinto, José R.

doi:10.3389/fphys.2017.00221

Cited by 19 publications

(10 citation statements)

References 78 publications

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“…2F). At saturating Ca 2+ , this HCM mutation was previously shown to be associated with increased myofibrillar ATPase activity (28, 49) and higher frequencies of oscillatory work during small amplitude, sinusoidal length perturbations (21). Both prior observations at maximal activation, together with the k TR measurements at maximal and submaximal levels of thin filament Ca 2+ -activation, are indicative of faster cross-bridge cycling.…”

Section: Discussionmentioning

confidence: 96%

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Structural and functional impact of troponin C-mediated Ca2+ sensitization on myofilament lattice spacing and cross-bridge mechanics in mouse cardiac muscle

Gonzalez-Martinez

Johnston

Landim-Vieira

et al. 2018

Journal of Molecular and Cellular Cardiology

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Acto-myosin cross-bridge kinetics are important for beat-to-beat regulation of cardiac contractility; however, physiological and pathophysiological mechanisms for regulation of contractile kinetics are incompletely understood. Here we explored whether thin filament-mediated Ca sensitization influences cross-bridge kinetics in permeabilized, osmotically compressed cardiac muscle preparations. We used a murine model of hypertrophic cardiomyopathy (HCM) harboring a cardiac troponin C (cTnC) Ca-sensitizing mutation, Ala8Val in the regulatory N-domain. We also treated wild-type murine muscle with bepridil, a cTnC-targeting Ca sensitizer. Our findings suggest that both methods of increasing myofilament Ca sensitivity increase cross-bridge cycling rate measured by the rate of tension redevelopment (k); force per cross-bridge was also enhanced as measured by sinusoidal stiffness and I/I ratio from X-ray diffraction. Computational modeling suggests that Ca sensitization through this cTnC mutation or bepridil accelerates k primarily by promoting faster cross-bridge detachment. To elucidate if myofilament structural rearrangements are associated with changes in k, we used small angle X-ray diffraction to simultaneously measure myofilament lattice spacing and isometric force during steady-state Ca activations. Within in vivo lattice dimensions, lattice spacing and steady-state isometric force increased significantly at submaximal activation. We conclude that the cTnC N-domain controls force by modulating both the number and rate of cycling cross-bridges, and that the both methods of Ca sensitization may act through stabilization of cTnC's D-helix. Furthermore, we propose that the transient expansion of the myofilament lattice during Ca activation may be an additional factor that could increase the rate of cross-bridge cycling in cardiac muscle. These findings may have implications for the pathophysiology of HCM.

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Section: Discussionmentioning

confidence: 96%

“…SS data were analyzed using R Studio Fast Fourier transform and reported in units of MPa. Relative pCa-force and pCa-SS relationships were fit using a 2-parameter, sigmoidal Hill equation, and normalized pCa-force relationships were fit using a 3-parameter, sigmoidal Hill equation as previously described (28).…”

Section: Methodsmentioning

confidence: 99%

Structural and functional impact of troponin C-mediated Ca2+ sensitization on myofilament lattice spacing and cross-bridge mechanics in mouse cardiac muscle

Gonzalez-Martinez

Johnston

Landim-Vieira

et al. 2018

Journal of Molecular and Cellular Cardiology

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“…Consistent with our findings, hypertrophic cardiomyopathy‐linked mutations differentially affected Ca 2+ sensitivity of force development in slow‐twitch and cardiac muscle fibres (Veltri et al . ). It is possible that interactions of ss/cTnC with the other constituents of the cTn complex in the heart (i.e.…”

Section: Discussionmentioning

confidence: 97%

Desensitizing mouse cardiac troponin C to calcium converts slow muscle towards a fast muscle phenotype

Tikunova¹,

Belevych

Doan

et al. 2018

The Journal of Physiology

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The missense mutation, D73N, in mouse cardiac troponin C has a profound impact on cardiac function, mediated by a decreased myofilament Ca sensitivity. Mammalian cardiac muscle and slow skeletal muscle normally share expression of the same troponin C isoform. Therefore, the objective of this study was to determine the consequences of the D73N mutation in skeletal muscle, as a potential mechanism that contributes to the morbidity associated with heart failure or other conditions in which Ca sensitivity might be altered. Effects of the D73N mutation on physiological properties of mouse soleus muscle, in which slow-twitch fibres are prevalent, were examined. The mutation resulted in a rightward shift of the force-stimulation frequency relationship, and significantly faster kinetics of isometric twitches and tetani in isolated soleus muscle. Furthermore, soleus muscles from D73N mice underwent a significantly greater reduction in force during a fatigue test. The mutation significantly reduced slow fibre mean cross-sectional area without affecting soleus fibre type composition. The effects of the mutation on Ca sensitivity of force development in soleus skinned slow and fast fibres were also examined. As expected, the D73N mutation did not affect the Ca sensitivity of force development in fast fibres but resulted in substantially decreased Ca sensitivity in slow fibres. The results demonstrate that a point mutation in a single constituent of myofilaments (slow/cardiac troponin C) led to major changes in physiological properties of skeletal muscle and converted slow muscle toward a fast muscle phenotype with reduced fatigue resistance and Ca sensitivity of force generation.

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“…Variants in TNNC1 can affect skeletal muscle function because cTnC is also expressed in slow skeletal muscle. The D145E mutant was reported to increase slow skeletal muscle ATPase activity at low and high calcium concentrations in reconstituted myofibrils (Veltri et al, 2017b). Although it is known that D145E does not affect myofilament calcium sensitivity in slow skeletal skinned fibers (Veltri et al, 2017b), it is unclear whether D132N has any effect on slow skeletal muscle function.…”

Section: Dissonance Between Clinical Outcomes and Mechanical Measuremmentioning

confidence: 99%

Familial Dilated Cardiomyopathy Associated With a Novel Combination of Compound Heterozygous TNNC1 Variants

Landim-Vieira

Johnston

et al. 2020

Front. Physiol.

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Familial dilated cardiomyopathy (DCM), clinically characterized by enlargement and dysfunction of one or both ventricles of the heart, can be caused by variants in sarcomeric genes including TNNC1 (encoding cardiac troponin C, cTnC). Here, we report the case of two siblings with severe, early onset DCM who were found to have compound heterozygous variants in TNNC1: p.Asp145Glu (D145E) and p.Asp132Asn (D132N), which were inherited from the parents. We began our investigation with CRISPR/Cas9 knockout of TNNC1 in Xenopus tropicalis, which resulted in a cardiac phenotype in tadpoles consistent with DCM. Despite multiple maneuvers, we were unable to rescue the tadpole hearts with either human cTnC wild-type or patient variants to investigate the cardiomyopathy phenotype in vivo. We therefore utilized porcine permeabilized cardiac muscle preparations (CMPs) reconstituted with either wild-type or patient variant forms of cTnC to examine effects of the patient variants on contractile function. Incorporation of 50% WT/50% D145E into CMPs increased Ca 2+ sensitivity of isometric force, consistent with prior studies. In contrast, incorporation of 50% WT/50% D132N, which had not been previously reported, decreased Ca 2+ sensitivity of isometric force. CMPs reconstituted 50-50% with both variants mirrored WT in regard to myofilament Ca 2+ responsiveness. Sinusoidal stiffness (SS) (0.2% peak-to-peak) and the kinetics of tension redevelopment (k TR ) at saturating Ca 2+ were similar to WT for all preparations. Modeling of Ca 2+ -dependence of k TR support the observation from Ca 2+ responsiveness of steady-state isometric force, that the effects on each mutant (50% WT/50% mutant) were greater than the combination of the two mutants (50% D132N/50% D145E). Further studies are needed to ascertain the mechanism(s) of these variants.

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Hypertrophic Cardiomyopathy Cardiac Troponin C Mutations Differentially Affect Slow Skeletal and Cardiac Muscle Regulation

Cited by 19 publications

References 78 publications

Structural and functional impact of troponin C-mediated Ca2+ sensitization on myofilament lattice spacing and cross-bridge mechanics in mouse cardiac muscle

Structural and functional impact of troponin C-mediated Ca2+ sensitization on myofilament lattice spacing and cross-bridge mechanics in mouse cardiac muscle

Desensitizing mouse cardiac troponin C to calcium converts slow muscle towards a fast muscle phenotype

Familial Dilated Cardiomyopathy Associated With a Novel Combination of Compound Heterozygous TNNC1 Variants

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