Changes in force and calcium sensitivity in the developing avian heart

1991 ◽  
Vol 69 (11) ◽  
pp. 1692-1697 ◽  
Author(s):  
R. E. Godt ◽  
R. T. H. Fogaça ◽  
T. M. Nosek
Keyword(s):  
Young Adult ◽  
Heart Development ◽  
Troponin I ◽  
Calcium Sensitivity ◽  
Extracellular Calcium ◽  
Contractile Apparatus ◽  
Chicken Heart ◽  
Twitch Force ◽  
Adult Heart ◽  
Isoform Switching

The aim of this study was to characterize the development of the contractile properties of intact and chemically skinned muscle from chicken heart and to compare these characteristics with those of developing mammalian heart reported by others. Small trabeculae were dissected from left ventricles of Arbor Acre chickens between embryonic day 7 and young adulthood (7 weeks post-hatching). At all ages, increasing extracellular calcium (0.45–3.6 mM) progressively increased twitch force of electrically stimulated trabeculae. Twitch force at 1.8 mM extracellular calcium, normalized to cross-sectional area, increased to a maximum at 1 day post-hatching, remained constant through 3 weeks post-hatching, but then decreased at 7 weeks post-hatching. The maximal calcium-activated force of trabeculae chemically skinned with Triton X-100 detergent increased to a maximum 2 days before the time of hatching and was not significantly changed up to 7 weeks post-hatching. Over the ages studied, average twitch force in 1.8 mM calcium was between 26 and 66% of maximal calcium-activated force after skinning, suggesting that the contractile apparatus is not fully activated during the twitch in normal Ringer. In skinned trabeculae, the calcium sensitivity of the contractile apparatus was higher in the embryo than in the young adult. These age-dependent changes in calcium sensitivity are correlated with isoform switching in troponin T. A decrease in pH from 7.0 to 6.5 decreased the calcium sensitivity of the contractile apparatus to a greater degree in skinned trabeculae from young adult hearts than in those from embryonic hearts. This change in susceptibility to acidosis is temporally associated with isoform switching in troponin I. Moreover, the decrease in maximal calcium-activated force with pH was also greater in trabeculae from young adult heart. Thus the contractile apparatus of embryonic chicken heart is less sensitive to the depressant effects of acidosis than that of the adult heart. These developmental changes in calcium sensitivity are analogous to those reported by others in mammalian heart.Key words: muscle contraction, heart development, acidosis, chicken, contractile proteins.

Developmental changes in passive stiffness and myofilament Ca2+ sensitivity due to titin and troponin-I isoform switching are not critically triggered by birth

2006 ◽  
Vol 291 (2) ◽  
pp. H496-H506 ◽  
Author(s):  
Martina Krüger ◽  
Thomas Kohl ◽  
Wolfgang A. Linke
Keyword(s):  
Guinea Pig ◽  
Heart Development ◽  
Troponin I ◽  
Collagen Matrix ◽  
Passive Stiffness ◽  
Adult Rats ◽  
Functional Changes ◽  
Fetal Rat ◽  
Isoform Switching ◽  
Species Specific

The giant protein titin, a major contributor to myocardial mechanics, is expressed in two main cardiac isoforms: stiff N2B (3.0 MDa) and more compliant N2BA (>3.2 MDa). Fetal hearts of mice, rats, and pigs express a unique N2BA isoform (∼3.7 MDa) but no N2B. Around birth the fetal N2BA titin is replaced by smaller-size N2BA isoforms and N2B, which predominates in adult hearts, stiffening their sarcomeres. Here we show that perinatal titin-isoform switching and corresponding passive stiffness (STp) changes do not occur in the hearts of guinea pig and sheep. In these species the shift toward “adult” proportions of N2B isoform is almost completed by midgestation. The relative contributions of titin and collagen to STp were estimated in force measurements on skinned cardiac muscle strips by selective titin proteolysis, leaving the collagen matrix unaffected. Titin-based STp contributed between 42% and 58% to total STp in late-fetal and adult sheep/guinea pigs and adult rats. However, only ∼20% of total STp was titin based in late-fetal rat. Titin-borne passive tension and the proportion of titin-based STp generally scaled with the N2B isoform percentage. The titin isoform transitions were correlated to a switch in troponin-I (TnI) isoform expression. In rats, fetal slow skeletal TnI (ssTnI) was replaced by adult carciac TnI (cTnI) shortly after birth, thereby reducing the Ca2+ sensitivity of force development. In contrast, guinea pig and sheep coexpressed ssTnI and cTnI in fetal hearts, and skinned fibers from guinea pig showed almost no perinatal shift in Ca2+ sensitivity. We conclude that TnI-isoform and titin-isoform switching and corresponding functional changes during heart development are not initiated by birth but are genetically programmed, species-specific regulated events.

Developmental expression of rat cardiac troponin I mRNA

Development ◽  
1991 ◽  
Vol 112 (4) ◽  
pp. 1041-1051
Author(s):  
S. Ausoni ◽  
C. De Nardi ◽  
P. Moretti ◽  
L. Gorza ◽  
S. Schiaffino
Keyword(s):  
Cardiac Troponin ◽  
Troponin I ◽  
Mammalian Species ◽  
Calcium Sensitivity ◽  
Cardiac Troponin I ◽  
Developmental Expression ◽  
Adrenergic Stimulation ◽  
Adult Heart ◽  
Amino Terminal ◽  
The Difference

We have isolated and sequenced a full-length cDNA clone of rat cardiac troponin I (TnI). The amino acid sequence of rat cardiac TnI is highly similar to that of other mammalian species in the portion of the molecule (residues 33–210) that is also homologous to skeletal muscle TnI isoforms. In contrast, a lower degree of similarity is present in the cardiac TnI-specific amino terminal extension (residues 1–32). This region contains a conserved serine residue that has been shown to be selectively phosphorylated by cAMP-dependent protein kinase. Cardiac TnI mRNA is weakly expressed in the 18-day fetal heart and accumulates in neonatal and postnatal stages. No difference can be demonstrated between TnI mRNAs present in fetal and postnatal heart by RNAase protection assays. The fetal and neonatal, but not the adult heart, contain significant amounts of slow skeletal TnI transcripts, detected by oligonucleotide probes specific for the 5′- and 3′-untranslated regions of slow skeletal TnI mRNA. In situ hybridization studies show that cardiac and slow skeletal TnI mRNAs are coexpressed in the rat heart from embryonic day 11 throughout fetal and perinatal stages. Changes in troponin isoform expression during development may be responsible for the difference in calcium sensitivity and in the response to beta-adrenergic stimulation between fetal and adult heart.

Regional Differences in Troponin I Isoform Switching during Rat Heart Development

1993 ◽  
Vol 156 (1) ◽  
pp. 253-264 ◽  
Author(s):  
Luisa Gorza ◽  
Simonetta Ausoni ◽  
Nicoletta Merciai ◽  
Kenneth E.M. Hastings ◽  
Stefano Schiaffino
Keyword(s):  
Heart Development ◽  
Rat Heart ◽  
Regional Differences ◽  
Troponin I ◽  
Isoform Switching

scholarly journals Computational modeling of Takotsubo cardiomyopathy: effect of spatially varying β-adrenergic stimulation in the rat left ventricle

2014 ◽  
Vol 307 (10) ◽  
pp. H1487-H1496 ◽  
Author(s):  
Sander Land ◽  
Steven A. Niederer ◽  
William E. Louch ◽  
Åsmund T. Røe ◽  
Jan Magnus Aronsen ◽  
...  
Keyword(s):  
Left Ventricle ◽  
Takotsubo Cardiomyopathy ◽  
Troponin I ◽  
Contractile Function ◽  
Single Cells ◽  
Apical Ballooning ◽  
Calcium Sensitivity ◽  
Takotsubo Syndrome ◽  
Adrenergic Stimulation ◽  
Inotropic Effects

In Takotsubo cardiomyopathy, the left ventricle shows apical ballooning combined with basal hypercontractility. Both clinical observations in humans and recent experimental work on isolated rat ventricular myocytes suggest the dominant mechanisms of this syndrome are related to acute catecholamine overload. However, relating observed differences in single cells to the capacity of such alterations to result in the extreme changes in ventricular shape seen in Takotsubo syndrome is difficult. By using a computational model of the rat left ventricle, we investigate which mechanisms can give rise to the typical shape of the ventricle observed in this syndrome. Three potential dominant mechanisms related to effects of β-adrenergic stimulation were considered: apical-basal variation of calcium transients due to differences in L-type and sarco(endo)plasmic reticulum Ca2+-ATPase activation, apical-basal variation of calcium sensitivity due to differences in troponin I phosphorylation, and apical-basal variation in maximal active tension due to, e.g., the negative inotropic effects of p38 MAPK. Furthermore, we investigated the interaction of these spatial variations in the presence of a failing Frank-Starling mechanism. We conclude that a large portion of the apex needs to be affected by severe changes in calcium regulation or contractile function to result in apical ballooning, and smooth linear variation from apex to base is unlikely to result in the typical ventricular shape observed in this syndrome. A failing Frank-Starling mechanism significantly increases apical ballooning at end systole and may be an important additional factor underpinning Takotsubo syndrome.

Abstract P459: Mavacamten And Danicamtiv Reverse Respective Contractile Abnormalities In Engineered Heart Tissue Models Of Hypertrophic And Dilated Cardiomyopathy

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Saiti S Halder ◽  
Lorenzo R Sewanan ◽  
Michael J Rynkiewicz ◽  
Jeffrey R Moore ◽  
William J Lehman ◽  
...  
Keyword(s):  
Dilated Cardiomyopathy ◽  
Calcium Sensitivity ◽  
Heart Tissue ◽  
Missense Mutations ◽  
Wild Type ◽  
Twitch Force ◽  
In Vitro Motility ◽  
Isometric Twitch ◽  
Engineered Heart Tissues

Missense mutations in alpha-tropomyosin (TPM1) can lead to development of hypertrophic (HCM) or dilated cardiomyopathy (DCM). HCM mutation E62Q and DCM mutation E54K have previously been studied extensively in experimental systems ranging from in vitro biochemical assays to animal models, although some conflicting results have been found. We undertook a detailed multi-scale assessment of these mutants that included atomistic simulations, regulated in vitro motility (IVM) assays, and finally physiologically relevant human engineered heart tissues. In IVM assays, E62Q previously has shown increased Calcium sensitivity. New molecular dynamics data shows mutation-induced changes to tropomyosin dynamics and interactions with actin and troponin. Human engineered heart tissues (EHT) were generated by seeding iPSC-derived cardiomyocytes engineered using CRISPR/CAS9 to express either E62Q or E54K cardiomyopathy mutations. After two weeks in culture, E62Q EHTs showed a drastically hypercontractile twitch force and significantly increased stiffness while displaying little difference in twitch kinetics compared to wild-type isogenic control EHTs. On the other hand, E54K EHTs displayed hypocontractile isometric twitch force with faster kinetics, impaired length-dependent activation and lowered stiffness. Given these contractile abnormalities, we hypothesized that small molecule myosin modulators to appropriately activate or inhibit myosin activity would restore E54K or E62Q EHTs to normal behavior. Accordingly, E62Q EHTs were treated with 0.5μM mavacamten (to remedy hypercontractility) and E54K EHTs with 0.5 μM danicamtiv (to remedy hypocontractility) for 4 days, followed by a 1 day washout period. Upon contractility testing, it was observed that the drugs were able to reverse contractile phenotypes observed in mutant EHTs and restore contractile properties to levels resembling those of the untreated wild type group. The computational, IVM and EHT studies provide clear evidence in support of the hyper- vs. hypo-contractility paradigm as a common axis that distinguishes HCM and DCM TPM1 mutations. Myosin modulators that directly compensate for underlying myofilament aberrations show promising efficacy in human in vitro systems.

Abstract 219: Histidine Substituted Cardiac Troponin I (a164h) Improves Survival And Protects Cardiac Contractility During Acute Hypoxia In The Aged Murine Heart.

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Nathan Palpant ◽  
Sharlene Day ◽  
Kimber Converso ◽  
Joseph Metzger
Keyword(s):  
Cardiac Troponin ◽  
Troponin I ◽  
Acute Hypoxia ◽  
Cardiac Contractility ◽  
Systolic Pressure ◽  
Calcium Sensitivity ◽  
The Elderly ◽  
Cardiac Troponin I ◽  
Pump Failure ◽  
Myofilament Calcium Sensitivity

Contractile dysfunction associated with ischemia is a significant cause of morbidity and mortality particularly in the elderly. Strategies designed to protect the aged heart from ischemia-mediated pump failure are needed. We have generated transgenic (Tg) mice expressing a modified form of adult cardiac troponin I, the Ca ++ -activated molecular switch of the myofilament. Consonant with the fetal isoform, this transgene encodes a histidine substitution (A164H) in the critical switch domain of TnI thus increasing myofilament calcium sensitivity in a pH-dependent manner. We hypothesized that aged mice (24 months), intrinsically susceptible to myocardial dysfunction, would retain improved cardiac contractility at baseline and during an acute hypoxic challenge by means of myofilament-mediated calcium sensitization. Methods/Results: At baseline, by echocardiography, Tg hearts had increased systolic function, with a 26% higher mean ejection fraction compared to nontransgenic (Ntg) mice: 75 ± 3% [Tg: n = 13] vs. 63 ± 4% [Ntg: n = 12], P < 0.05, with no differences in diastolic function between the groups. To study the effects of acute hypoxia on cardiac hemodynamics mice underwent microconductance Millar catheterization while ventilated with 12% oxygen. Aged Tg mice had improved survival compared to Ntg mice: time to pump failure (65% of baseline peak systolic pressure) 11.59 ± 1.25 min. [Tg: n = 3] vs. 4.11 ± 1.90 min. [Ntg: n = 3], P < 0.05. After four minutes of hypoxia, Tg mice had markedly improved cardiac contractility compared to Ntg mice with increased stroke volume (30.05 ± 4.49 uL [Tg] vs. 13.23 ± 3.21 uL [Ntg], P < 0.05), end systolic pressure (106.09 ± 11.81 mmHg [Tg] vs. 64.49 ± 4.05 mmHg [Ntg], P < 0.05) and rate of positive left ventricular pressure development (12958.66 ± 2544.68 mmHg/sec [Tg] vs. 5717.00 ± 745.67 mmHg/sec [Ntg], P = 0.05). Conclusion: An alteration in myofilament calcium sensitivity via a pH-responsive histidine button in cardiac troponin I augments baseline heart function in Tg mice over their lifetime. During acute hypoxia, cTnI A164H improves survival in aged mice by maintaining cardiac contractility, and thus holds promise for the design of gene therapeutics to treat pump failure associated with acute ischemic events in the elderly.

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